Aggregation behaviour of chiral ionic liquids

Article abstract of DOI:10.1016/j.tetasy.2009.10.010

The diastereomeric ionic liquid (IL) (1R,2S)-ephedrinium (RS)-methoxytrifluorophenylacetate 1 was synthesized and its aggregation behavior and diastereomeric interaction were investigated using two independent methods. The aggregation number of the IL in

Full text of DOI:10.1016/j.tetasy.2009.10.010

Tetrahedron: Asymmetry 20 (2009) 2479–2481
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Aggregation behaviour of chiral ionic liquids
*
Peter S. Schulz , Karola Schneiders, Peter Wasserscheid
Chair of Chemical Reaction Engineering, Friedrich-Alexander Universität Erlangen-Nürnberg, Egerlandstr. 3, 91058 Erlangen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereomeric ionic liquid (IL) (1R,2S)-ephedrinium (RS)-methoxytrifluorophenylacetate 1 was syn-
thesized and its aggregation behavior and diastereomeric interaction were investigated using two inde-
pendent methods. The aggregation number of the IL in methylene chloride was determined by diffusion
ordered NMR spectroscopy. Furthermore the concentration dependence of the signal split of the two dia-
stereomeric ILs (1R,2S)-ephedrinium (R)-methoxytrifluorophenylacetate and (1R,2S)-ephedrinium (S)-
methoxytrifluorophenylacetate was measured and could be linked to the aggregation number.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 30 July 2009
Accepted 7 October 2009
Available online 10 November 2009
1. Introduction
the temperature and viscosity can be easily measured, c has to be
evaluated in a more complex procedure. An acceptable semiempir-
Chiral ionic liquids (CILs) are a versatile and interesting subclass
of ionic liquids (ILs). They have been successfully used in analytical
applications such as stationary phases in gas chromatography,1,2 or
as electrolytes in capillary electrophoresis,3–6 as well as in asym-
metric synthesis. Prominent examples are the Diels–Alder reac-
tion,7–9 the Baylis–Hillman reaction,10–12 Michael additions,13 and
asymmetric hydrogenations.14–16 CILs have also been used as effec-
tive organocatalysts.17–19
ical approach to estimate c through Eq. (2) has been developed by
Wirtz et al. using microfriction theory:26,27
2:234
solv
D ¼ kT½1 þ 0:695r
=rHꢁ=6pgrH
ð2Þ
Here rsolv is the hydrodynamic radius of the solvent and rH is the
hydrodynamic radius of the solute. Next, c is determined via itera-
tion with the calculated radius of the solute as a starting value.
A simplified procedure for metallorganic ionic species has
recently been described.28 We adapted this procedure to an ionic
liquid solution. Provided that the hydrodynamic radius rsHt of the
solvent in which the ionic liquid is dissolved is known and can
be used as an internal standard, the Stokes–Einstein-Equation lar-
gely simplifies to:
2. Results and discussion
All these examples suggest that high stereocontrol is obtained
when ionic transition states are present during the reaction in ques-
tion and that the chiral induction from a charged species to a neu-
tral intermediate is much less effective. The understanding of
specific cation–anion interactions is therefore crucial for designing
a system in which the transfer of chiral information is maximized. A
very elegant possibility to investigate these interionic interactions
in ILs is diffusion ordered NMR spectroscopy (DOSY-NMR). This
method, which has been successfully applied to a variety of ILs in
the recent years,20–25 provides access to the individual self-diffu-
sion coefficients of cation (D+) and anion (Dꢀ) of an ionic liquid.
As the self-diffusion coefficient of an ion is to a large extent a
function of its size and shape, it is possible to estimate its hydrody-
namic radius rH from the measured coefficients via the Stokes–Ein-
stein-Equation:
Dsa=Dst ¼ cstrHst=csarsHa
ð3Þ
in which the suffix sa stands for the sample and st for the standard
value. As the diffusion coefficients are measured and c-values deter-
mined via iteration, the hydrodynamic radius of the sample mole-
cule can be easily determined. Under the assumption of spherical
species, the volume of the diffusing species can now be determined.
Furthermore, the so determined volumina can be compared to those
obtained from the theoretical approaches. In the case of an ionic li-
quid the ratio of the measured volume of the anion or cation to the
IP
calculated volume of the ion pair V
can thus be determined, rep-
calc
resenting the average aggregation numbers Nꢀ and N+, respectively.
Nꢀ=þ ¼ Vꢀ=þ=VIP
ð4Þ
calc
D ¼ kT=cpgrH
ð1Þ
An aggregation number of N = 1 consequently describes a contact
ion pair, a value of N = 0.5 isolated and solvated ions, whereas high-
er numbers, N >1, can be interpreted as the formation of higher
aggregates.
in which k represents the Boltzmann-constant, T is the temperature,
c is a numerical factor, and is the viscosity of the solution. While
g
We have investigated the dissociation and aggregation behavior
of the doubly chiral ionic liquid (1R,2S)-ephedrinium (RS)-meth-
* Corresponding author. Tel.: +49 9131 8527431; fax: +49 9131 27421.
E-mail address: peter.schulz@crt.cbi.uni-erlangen.de (P.S. Schulz).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.010

2480
P. S. Schulz et al. / Tetrahedron: Asymmetry 20 (2009) 2479–2481
ionic liquid is still 1 and it starts to increase significantly with high-
CH3
O
er concentrations, which indicates the formation of aggregates.
Going to lower concentrations resulted in no further significant de-
crease in the aggregation number. This indicates that CD2Cl2 is not
able to stabilize the single solvated ions of this specific ionic liquid
(see Fig. 2).
MeO
F3C
HO
(R)
CH3
S)
(
N
O
H2
As we have shown in our earlier work,29 the conjugate base of
racemic Mosher’s acid is a suitable probe molecule for the diaste-
reomeric interaction between ionic species. Combining the anion
of this racemic acid with an enantiopure cation gives rise to two
signals of the CF3-moiety in 19F NMR spectroscopy. This chemical
shift difference qualitatively reflects the strength of the diastereo-
meric interaction between cation and anion.
We measured the peak separation as a function of the concen-
tration of 1 in CD2Cl2. This study supports the findings of our
earlier work as the peak separation increases when increasing
the concentration. Interestingly, a significant peak separation could
only be found from a minimum concentration of c >4 ꢂ 10ꢀ2 mol/l.
This is the same concentration for which we have shown the aggre-
gate formation to start.
(RS)
1
Figure 1. (1R,2S)-Ephedrinium (RS)-methoxytrifluorophenylacetate.
oxytrifluorophenylacetate (ephedrinium mosherate) 1 in CD2Cl2
as described above (see Fig. 1). A concentration range from 2.5 ꢂ
10ꢀ3 mol/l to 6.4 ꢂ 10ꢀ1 mol/l was scanned, with the higher con-
centration being limited by the IL’s solubility.
Below a concentration of 1 ꢂ 10ꢀ3 mol/L a DOSY-measurement
is problematic due to the poor signal to noise ratio and the very ra-
pid decay of the signal intensity with increasing gradient strength.
0
IP
The volume of an ion pair (V ) of 1 was determined as 359.58 ÅA3
calc
using a semiempirical simulation tool (Materials studio, VAMP,
AM1-dataset). As can be seen from Table 1, both the aggregation
numbers N+ and Nꢀ increase when increasing the concentration
of the IL above a critical concentration of 4 ꢂ 10ꢀ2 mol/l. This is
the critical concentration at which the aggregation number of the
A pronounced concentration dependency of signal splitting for
diastereomeric electrolytes in solutions has often been de-
scribed.29–33 As a whole, these works indicate a general trend: At
low concentrations, the split increases with increasing amount of
electrolyte until a plateau is reached. At higher concentrations
Table 1
Diffusion coefficients and aggregation numbers of 1 in CD2Cl2
Concentration
(mol/l)
Peak separation of
enantiomers (Hz)
Diffusion coefficient (m2/s)
Anion
N+
Nꢀ
Cation
CD2Cl2
6.40 ꢂ 10ꢀ1
3.20 ꢂ 10ꢀ1
1.60 ꢂ 10ꢀ1
8.00 ꢂ 10ꢀ2
4.00 ꢂ 10ꢀ2
3.00 ꢂ 10ꢀ2
2.00 ꢂ 10ꢀ2
1.00 ꢂ 10ꢀ2
5.00 ꢂ 10ꢀ3
2.50 ꢂ 10ꢀ3
23.88
20.21
15.62
11.94
5.51
None
None
None
None
None
5.20 ꢂ 10ꢀ10
8.27 ꢂ 10ꢀ10
1.13 ꢂ 10ꢀ9
1.49 ꢂ 10ꢀ9
1.96 ꢂ 10ꢀ9
1.68 ꢂ 10ꢀ9
2.05 ꢂ 10ꢀ9
1.91 ꢂ 10ꢀ9
1.86 ꢂ 10ꢀ9
1.86 ꢂ 10ꢀ9
5.10 ꢂ 10ꢀ10
8.53 ꢂ 10ꢀ10
1.13 ꢂ 10ꢀ9
1.50 ꢂ 10ꢀ9
1.97 ꢂ 10ꢀ9
1.68 ꢂ 10ꢀ9
2.04 ꢂ 10ꢀ9
1.89 ꢂ 10ꢀ9
1.84 ꢂ 10ꢀ9
1.84 ꢂ 10ꢀ9
2.21 ꢂ 10ꢀ9
3.23 ꢂ 10ꢀ9
3.74 ꢂ 10ꢀ9
4.12 ꢂ 10ꢀ9
4.62 ꢂ 10ꢀ9
4.43 ꢂ 10ꢀ9
4.83 ꢂ 10ꢀ9
4.65 ꢂ 10ꢀ9
4.56 ꢂ 10ꢀ9
4.56 ꢂ 10ꢀ9
3.5
2.8
1.9
1.2
0.9
1.1
0.9
0.9
0.9
0.9
3.7
2.6
1.9
1.2
0.9
1.1
0.9
1.0
1.0
1.0
Figure 2. Peak separation and aggregation numbers against concentration of 1 in CD2Cl2.

P. S. Schulz et al. / Tetrahedron: Asymmetry 20 (2009) 2479–2481
2481
the split diminishes again. This behavior was interpreted as the
Acknowledgments
subsequent aggregation of isolated ions to contact ion pairs and
then to quadruples and/or higher aggregates. Efficient peak split-
ting was attributed to ion pair formation. We have now demon-
strated that this is not necessarily the case. Obviously, in a
contact ion pair of 1 the diastereomeric interaction is not strong
enough to allow differentiation by NMR spectroscopy between
the (R,S)(R)- and the (R,S)(S)-diastereomer. We suggest that a dis-
tinct arrangement of cation to anion is necessary to allow strong
interaction. In the case of 1 this arrangement is enabled only in
the aggregates.
The authors wish to thank the German Science Foundation
(DFG) for funding this work within its priority program 1191 ‘Ionic
Liquids’.
References
1. Berthod, A.; He, L.; Armstrong, D. W. Chromatographia 2001, 53, 63–68.
2. Ding, J.; Welton, T.; Armstrong, D. W. Anal. Chem. 2004, 76, 6819–6822.
3. Rizvi, S. A. A.; Shamsi, S. A. Anal. Chem. 2006, 78, 7061–7069.
ˇ
´
ˇ
4. Maier, V.; Horáková, J.; Petr, J.; Drahonovsky, D.; Ševcík, J. J. Chromatogr., A
2006, 1103, 337–343.
5. François, Y.; Varenne, A.; Juillerat, E.; Villemin, D.; Gareil, P. J. Chromatogr., A
2007, 1155, 134–141.
3. Conclusion
6. Tran, C. D.; Mejac, I. J. Chromatogr., A 2008, 1204, 204–209.
7. Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P. Tetrahedron Lett. 1997, 38,
3097–3100.
8. Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green Chem. 1999, 1, 23.
9. Doherty, S.; Goodrich, P.; Hardacre, C.; Knoght, J. G.; Nguyen, M. T.; Pârvulescu,
V. I.; Paun, C. Adv. Synth. Catal. 2007, 349, 951–963.
10. Gausepohl, R.; Buskens, P.; Kleinen, J.; Bruckmann, A.; Lehmann, C. W.;
Klankermeyer, J.; Leitner, W. Angew. Chem., Int. Ed. 2006, 45, 3689–3692.
11. Pégot, B.; Vo-Thanh, G.; Loupy, A. Tetrahedron Lett. 2004, 45, 6425–6428.
12. Garre, S.; Parker, E.; Ni, B.; Headley, A. D. Org. Biomol. Chem. 2008, 6, 3041–
3043.
13. Zhang, Q.; Ni, B.; Headley, A. D. Tetrahedron 2008, 64, 5091–5097.
14. Schmitkamp, M.; Chen, D.; Leitner, W.; Klankermeyer, J.; Franciò, G. Chem.
Commun. 2007, 4012–4014.
15. Schulz, P. S.; Müller, N.; Bösmann, A.; Wasserscheid, P. Angew. Chem., Int. Ed.
2007, 46, 1293–1295.
16. Schneiders, K.; Bösmann, A.; Schulz, P. S.; Wasserscheid, P. Adv. Synth. Catal.
2009, 351, 432–440.
17. Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed. 2006,
45, 3093–3097.
18. Luo, S.; Zhang, L.; Mi, X.; Qiou, Y.; Cheng, J.-P. J. Org. Chem. 2007, 72, 9350–
9352.
19. Ni, B.; Zhang, Q.; Headley, A. D. Tetrahedron Lett. 2008, 49, 1249–1252.
20. Hayamizu, K.; Aihara, Y.; Arai, S.; Garcia Martinez, C. J. Phys. Chem. B 1999, 103,
519.
21. Noda, A.; Hayamizu, K.; Watanabe, M. J. Phys. Chem. B 2001, 105, 4603.
22. Giernoth, R.; Bankmann, D. Eur. J. Org. Chem. 2005, 4529.
23. Nama, D.; Kumar, P. G. A.; Pregosin, P. S.; Geldbach, T. J.; Dyson, P. J. Inorg. Chim.
Acta 2006, 359, 1907.
24. Saito, Y.; Umecky, T.; Niwa, J.; Sakai, T.; Maeda, S. J. Phys. Chem. B 2007, 11794.
25. Annat, G.; MacFarlane, D. F.; Forsyth, M. J. Phys. Chem. B 2007, 9018.
26. Gierer, A.; Wirtz, K. Z. Naturforsch., A 1953, 8, 522.
27. Spernol, A.; Wirtz, K. Z. Naturforsch., A 1953, 8, 532.
28. Zuccaccia, D.; Macchioni, A. Organometallics 2005, 24, 3476–3486.
29. Wasserscheid, P.; Bösmann, A.; Bolm, C. Chem. Commun. 2002, 201–202.
30. Kumar, V.; Pei, C.; Olsen, C. E.; Schäffer, S. J. C.; Parmar, V. S.; Malhotra, S. V.
Tetrahedron: Asymmetry 2008, 19, 664–671.
Our work demonstrates that the concentration range that al-
lows effective chirality transfer in synthetic applications can be
rationalized by NMR spectroscopy. We anticipate that by using
the herein described technique it will be possible to predict for a
given reaction of a prochiral ion in a chiral ionic liquid the suitable
concentration range for potential chirality transfer.
4. Experimental
NMR experiments were carried out with a Jeol ECX 400 MHz
spectrometer with a 2-chanel (HF, LF)-probe. Spectra were refer-
enced to the solvent. The optical rotations were recorded with a
Polartronic E, Schmidt + Haensch.
(1R,2S)-Ephedrinium (RS)-methoxytrifluoromethylphenyl-ace-
tate 1 was synthesized by adding equimolar amounts of (RS)-meth-
oxytrifluoromethylphenylacetic
acid
to
(1R,2S)-ephedrine
dissolved in dichloromethane. After stirring for 1 h the solvent
was removed in vacuo and the product was obtained as white solid
in quantitative yield. ½a D20
ꢁ
¼ þ0:4 (c 1.0, CH2Cl2). 1H NMR (CDCl3,
400 MHz, ppm): d = 0.94 (d, 3H, CH–CH3, 3-H, 3J = 6.8 Hz), 2.44 (s,
3H, OCH3), 2.99 (dq, 1H, CH–CH3, 3J = 1.7 Hz, 3J = 6.8 Hz), 3.51 (d,
3H, N–CH3, 3J = 7.0 Hz), 5.28 (d, 1H, CH–OH, 3J = 1.7 Hz), 7.23–
7.33 (m, 8H, Phenyl-H), 7.62–7.67 (m, 2H, Phenyl-H).
13C NMR (CDCl3, 100.4 MHz, ppm): d = 8.80 (d, CH–CH3), 30.89
(d, OCH3), 55.04 (d, N–CH3), 61.63 (d, CH–CH3), 70.24 (d, CH–OH),
85.36 (u, quart., CF3–C, 3J = 26 Hz), 124.63 (CF3, 1J = 287 Hz),
125.74 (d, Phenyl-C), 127.57, 127.73, 127.79 (d, Phenyl-C), 128.20
(d, Phenyl-C), 128.43 (d, Phenyl-C), 128.91 (d, Phenyl-C), 135.26 (u,
CF3–C–C), 139.84 (u, CH–C), 171.79 (u, CO). 19F NMR (CDCl3,
376.3 MHz, ppm): d = ꢀ69.78 (CF3). Anal. Calcd for C20H24F3NO4: C,
60.14; H, 6.06; F, 14.27; N, 3.51; O, 16.02. Found: C, 60.11; H,
6.14; N, 3.40.
ˇ ˇ
31. Navrátilová, H.; de Gelder, R.; Kríz, Z. J. Chem. Soc., Perkin Trans. 2 2002, 2093–
2099.
32. Villani, F. J.; Costanzo, M. J.; Inners, R. R.; Mutter, M. S.; McClure, D. E. J. Org.
Chem. 1986, 51, 3715–3718.
33. Buckson, R. L.; Smith, S. G. J. Phys. Chem. 1964, 68, 1875–1878.
The 13C-signal for CF3-moiety is not detectable with standard techniques using
1000 scans. It was detected by using a HF-HETCOR-experiment and an experiment
with 10,000 scans using Fe(acac)3 as a relaxation agent.