Synthesis and properties of ionic liquids derived from the 'chiral pool'

Article abstract of DOI:10.1039/b109493a

New chiral ionic liquids have been synthesised which are directly derived from the 'chiral pool' and therefore readily available in kg scale; NMR-measurements indicate that these liquids may be interesting solvents for enantioselective reactions and useful in chiral separation techniques.

Full text of DOI:10.1039/b109493a

Synthesis and properties of ionic liquids derived from the ‘chiral pool’†
a
a
b
Peter Wasserscheid,* Andreas Bösmann and Carsten Bolm
a
Institut für Technische und Makromolekulare Chemie, RWTH Aachen, Worringer Weg 1 D-52074.
Aachen, Germany. E-mail: Wasserscheidp@itmc.rwth-aachen.de; Fax: (+49) 241 80-22177; Tel: (+49)
2
41 88-26492
b
Institut für Organische Chemie, RWTH Aachen, Prof.-Pirlet-Straße 1 D-52074. Aachen, Germany
Received (in Cambridge, UK) 18th October 2001, Accepted 4th December 2001
First published as an Advance Article on the web 7th January 2002
New chiral ionic liquids have been synthesised which are
directly derived from the ‘chiral pool’ and therefore readily
available in kg scale; NMR-measurements indicate that
these liquids may be interesting solvents for enantioselective
reactions and useful in chiral separation techniques.
Even if 1a and 1b could be prepared in multi-gram scale, the
relatively low overall yield of the four step synthesis is still a
concern for the practical use of type 1 ionic liquids. Moreover,
the oxazolinium cation was found to be of low stability under
acidic conditions where ring opening was observed to a large
extent.
Ionic liquids (ILs) are low melting ( < 100 °C) salts which
represent a new class of non-molecular, ionic solvents.1
Nowadays, ILs are widely accepted as–often greener–alter-
natives to classical organic solvents in chemical transformations
These considerations led to the development of IL 2 which is
more readily obtained from the alkaloid ephedrine in a three
step synthesis. Leuckart–Wallach reaction followed by alkyla-
–3
2 4
tion with Me SO and ion exchange in aqueous solution
(
for reviews see refs 1–3) and separation techniques (e.g.
resulted in 80% overall yield for the synthesis of 2.§
4
5
extraction, chromatography ). Over the past few years the
range of known and available ILs has been expanded so that
many different candidates are accessible and even commer-
cially available today.6
Surprisingly, the number of published examples for chiral ILs
has been very limited so far. Howarth and co-workers described
the use of chiral imidazolium cations in Diels–Alder reactions.7
However, the synthesis of these systems required an expensive
chiral alkylating agent. The use of ILs with chiral anions is
somehow more obvious since some of these are readily
available as sodium salts. For example, Seddon et al. investi-
gated Diels–Alder reactions in lactate ILs.8
In the present paper, we describe for the first time ILs with
chiral cations which are directly derived from the ‘chiral pool’.
These systems have been designed to meet the following
criteria: a) easy preparation by direct synthesis in enantiopure
form (up-scaling into kg scale possible); b) melting point < 80
Compound 2 has a melting point of 54 °C and is stable up to
23
150 °C under high vacuum conditions (10
mbar). As
expected, it shows a miscibility gap with water which generally
allows its application for extractions from aqueous solutions.
The quest for room temperature liquid ILs with chiral cation
resulted in the synthesis of IL 3.
°
C; c) thermal stability up to 100 °C; d) good chemical stability
vs. water and common organic substrates; e) relatively low
viscosity.
Three different groups of chiral cations 1–3 have been
identified which fulfil–at least to a large extent–these require-
ments.
Compound 3 is obtained in a very similar manner as 2.¶ It was
prepared in 75% overall yield and is still a liquid at 218 °C. At
room temperature, its viscosity is surprisingly low (h = 0.155
Pa*s at 20 °C). As 2, this chiral IL shows good thermal stability
2
3
up to 150 °C under high vacuum conditions (10 mbar). The
1
9
enantiopurity of 2 and 3 has been confirmed by F-NMR
spectroscopy after esterification of 2 and 3 with (S)-Mosher’s
acid chloride. The synthesis of 3 has been carried out on a kg
scale without loss in yield or enantiopurity.
Ionic liquids of type 1 can be prepared by alkylation of the
corresponding oxazoline with an alkylbromide followed by
anion exchange. The oxazoline is prepared according to known
procedures by reaction of the (S)-valinol with an aliphatic acid.9
After having successfully established the synthesis of type
1
–3 ionic liquids our interest was to evaluate the usefulness of
these compounds for enantioselective reactions and separation
techniques. However, instead of screening specific applications
we decided to choose a more general approach. Our aim was to
investigate solutions of racemic substrates in the chiral ionic
liquids by NMR spectroscopy and to look for diasteriomeric
interactions between substrate and IL. Obviously, those inter-
actions would be essential for all kinds of chirality transfer from
the chiral IL onto the substrate.
(
S)-Valinol is easily accessible from (S)-valine by reduction
0,11
with NaBH
4
–H
2
SO
4
in THF.1
In this way 1a has been
obtained in 40% overall yield (referred to valine).‡ Its melting
point is 63 °C (79 °C for 1b). The enantiopurity of 1a has been
confirmed by 19F-NMR spectroscopy after basic hydrolysis of
1a and reaction with (S)-Mosher’s acid chloride.
In detail, these interactions have been probed by 19F-NMR
spectroscopy using a racemic mixture of Mosher’s acid sodium
†
Electronic supplementary information (ESI) available: characterisation of
compounds 1a, 2 and 3. See http://www.rsc.org/suppdata/cc/b1/b109493a/
2
00
CHEM. COMMUN., 2002, 200–201 This journal is © The Royal Society of Chemistry 2002

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asymmetric synthesis and catalysis as well as NMR spectros-
copy. Furthermore, the application of chiral ILs as mobile or
stationary phases in chromatography is under investigation.
Notes and references
‡
Synthesis of 1a: 97 g (S)-valinol (94% yield) was obtained from 117.15 g
10
(1 mol) (S)-valine following the procedure of Masamune et al. According
9
to prior work, 103.16 g (1 mol) valinol was reacted with 74.08 g (1 mol)
propionic acid to yield 67.8 g (S)-2-ethyl-4-isopropyloxazolin (48% yield).
2
9 g (0.2 mol) of the latter was mixed with 62 g pentyl bromide (0.4 mol)
and refluxed for 2 d. The remaining pentylbromide was removed under high
vacuum to yield 89.2 g (0.196 mol, 98% yield) of crude (S)-2-ethyl-
3
-pentyl-4-isopropyloxazolinium bromide. 7 g (24 mmol) of the ox-
azolinium bromide was dissolved in 50 ml water and 6.6 ml (31 mmol) of
a 65% hexafluorophosphoric acid was added. The resulting precipitate was
washed with water and dried under high vacuum to give 7.8 g (91% yield)
(
S)-2-ethyl-3-pentyl-4-isopropyloxazolinium hexafluorophosphate (mp =
1
6
3 °C). H-NMR (300 MHz), CDCl
(7H), 1.68 (m, 2H), 2.22 (m, 1H); 2.73 (m, 2H), 3.40 (m, 1H), 3.63 (m, 1H),
.46 (m, 1H), 4.64 (m, 1H), 4.90 (m, 1H); 13C-NMR (75 MHz), CDCl
TMS: d = 7.99, 13.27, 13.45, 17.38, 19.95, 21.72, 26.04, 26.50, 28.13,
3
–TMS: d = 0.78–1.10 (9H), 1.18–1.33
Fig. 1 19F-NMR of rac-Mosher’s acid sodium salt in 2.
4
3
–
salt as substrate and 2 as chiral ionic liquid.∑ One of the recorded
19
4
2
5.34, 65.53, 71.11, 178.63; F-NMR (282 MHz), CDCl
72.9 (d, J = 710 Hz); 31P-NMR (121 MHz), CDCl
: d = 2143.2 (hept,
J = 710 Hz).
3 3
–CCl F: d =
spectra is presented in Fig. 1.
3
3
The split of the signal related to the CF -group of the racemic
substrate clearly demonstrates that the substrate has been
dissolved in a chiral environment. Moreover, the extent of peak
splitting can be assigned to the strength of the diastereomeric
interactions. In this regard it is interesting to note that the
§
Synthesis of 2: (2)-N-Methylephedrine was prepared from (2)-ephedrine
12
according to known literature in 87% yield. 17.9 g (0.1 mol) N-
methylephedrine was dissolved in 50 ml dichloromethane and 12.6 g (0.1
mol) Me SO was slowly added. The solvent was removed under reduced
pressure and the residue dissolved in water. Addition of an aqueous solution
of 31.6 g (0.11 mol) Li[(CF SO N] led to the separation of an ionic liquid
2
4
chemical shift difference for the two diastereomeric CF
3
-groups
depends on the concentration of the ionic liquid in the NMR
solvent. Moreover, the influence of water added to the chiral
ionic liquid is of major influence for the extent of signal splitting
3
2 2
)
phase which was washed three times with 50 ml water. Drying of the ionic
liquid phase at 100 °C under high vacuum resulted in 43.7 g (92% yield)
(
5
3
2)-N,N-dimethylephedrinium-bis(trifluoromethanesulfon)imidate (mp =
(
Fig. 2).
1
4 °C). H-NMR (300 MHz), DMSO–TMS: d = 1.16 (3H, d, J = 6.4 Hz),
In conclusion, we could demonstrate that ILs with chiral
.22 (9H, s), 3.65 (1H, dq, J = 6.4 Hz, J = 6.8 Hz), 5.41 (1H, d, J = 6.8
cations can readily be prepared in enantiopure form from the
‘
13
Hz), 6.06 (1H, s), 7.19–7.31 (5H, m); C-NMR (75 MHz), DMSO–TMS:
d = 6.5, 51.5, 68.5, 73.6, 119.5 (q, J = 321.6 Hz), 125.8, 127.4, 128.1,
chiral pool’. Some of the tested systems combine high thermal
stability with low viscosity which makes them interesting
solvent candidates for many applications in chemical synthesis
and separation techniques. The general possibility of diaster-
eomeric interactions between an enantiopure IL and a chiral
substrate has been demonstrated by NMR spectroscopy.
From this starting point, more research to fully evaluate the
potential of these new chiral systems in synthetic and analytical
applications is actually ongoing in our laboratories. In detail, we
are currently studying the use of chiral ILs in the resolution of
racemates by co-crystallisation or extraction, and as solvents for
141.9; 19F-NMR (282 MHz), DMSO–CCl F: d = 279.3.
3
¶ Synthesis of 3: 3 (mp < 218 °C) was prepared from (R)-2-aminobutan-
1-ol in 75% overall yield following the method described for the synthesis
1
of 2. H-NMR (300 MHz), CD
3
CN/TMS: d = 1.03 (3H, t, J = 7.2Hz), 1.83
(
2H, m), 3.06 (9H, s), 3.09 (1H, m), 3.4 (1H, s), 3.83 (1H,m), 4.2 (1H, m);
13
C-NMR (75 MHz), CD
q, J = 321Hz). 19F-NMR (282 MHz), CD
NMR Experiment: 10 mg of sodium-(S)-2-methoxy-2-(trifluoromethyl)-
3
CN/TMS: d = 11.4, 18.7, 53.2, 57.7, 77.7, 120.8
(
3
CN/CCl F: d = 278.9.
3
∑
phenylacetate was dissolved in 150 mg of 2. This mixture was dissolved in
0
2 2
.35 ml CD Cl and the spectrum was recorded. For the spectrum in water-
saturated IL, 0.2 ml water was added to the above mentioned mixture and
the mixture was shaken. The spectrum of the IL layer was recorded.
1
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