Design and synthesis of hydrophobic and chiral anions from amino acids as precursor for functional ionic liquids

Article abstract of DOI:10.1039/b606613e

Hydrophobic ionic liquids composed of tetrabutylphosphonium cation and chiral anions derived from amino acids modified with trifluoromethane sulfonyl groups have been synthesized using a simple method. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606613e

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Design and synthesis of hydrophobic and chiral anions from amino acids
as precursor for functional ionic liquids{
Kenta Fukumoto and Hiroyuki Ohno*
Received (in Cambridge, UK) 10th May 2006, Accepted 30th May 2006
First published as an Advance Article on the web 14th June 2006
DOI: 10.1039/b606613e
amino group on an a-carbon led to interaction between
component ions. ILs are more useful in applications when they
have lower viscosity and stability over a wide temperature range.
In the present work, we prepared chiral and hydrophilic amino
acid derivatives by introducing both the trifluoromethane sulfonyl
group and methyl ester group.
Hydrophobic ionic liquids composed of tetrabutylphospho-
nium cation and chiral anions derived from amino acids
modified with trifluoromethane sulfonyl groups have been
synthesized using a simple method.
Ionic liquids (ILs)1 are designer liquids with the possibility of our
choosing their physico-chemical properties and solvent properties
such as polarity,2 melting point,3 ionic conductivity,4 and viscosity.
Choice of component organic ions may generate ILs suitable for
specific tasks.5 Our recent investigations strongly suggest the value
of amino acids as components of ILs; we have already reported
some ILs having natural amino acids as anion, hereafter referred
to as amino acid ILs (AAILs).6 Physico-chemical properties of
AAILs, including thermal properties, viscosity, polarity, and
solubility of organic compounds, are strongly affected by the
properties of the amino acids. Use of natural amino acids as
component ions also make AAILs environmentally friendly, with
biodegradability7 and reduced toxicity.8 AAILs furthermore
provide a chiral environment without any complicated procedure,
by simply neutralizing the chiral amino acids with the correspond-
ing onium hydroxide, such as [emim][OH]. Further design for
function of ILs is expected to be possible by chemical modification
of the amino group, carboxyl group, or various functional groups
on the side chain of the amino acid.9
Amino acid was added to methanol which had been pre-treated
with thionyl chloride at 0 uC, and then stirred overnight. Among
natural amino acids, L-alanine, L-valine, or L-leucine were used as
starting materials, because they have no functional group in the
side chain. The effect of alkyl chain length on the properties of ILs
should also be considered, so as to eliminate the effect of
additional interactions such as hydrogen bonding. The mixture
was then concentrated under reduced pressure. The resulting white
solid was suspended in dichloromethane and a bimolar amount of
triethylamine was added with stirring. Trifluoromethanesulfonic
anhydride dissolved in dichloromethane was added to the mixture
under a dry nitrogen atmosphere at 278 uC, and the mixture then
stood overnight at room temperature. The resulting solution was
washed with dilute hydrochloric acid and saturated aqueous
sodium chloride. Then concentrated dichloromethane solution was
added in vacuo, giving rise to an oil which was purified by column
chromatography on silica gel (MeOH/CHCl3 = 1 : 5) to provide
the corresponding N-trifluoromethane sulfonyl amino acid methyl
ester (Scheme 1). A similar synthetic procedure of the introduction
of a trifluoromethanesulfonyl group to the amino group on some
peptides has been reported by Radom et al.12 These amino acid
derivatives were obtained as hydrophobic white crystals (see
note{1 and ESI{).
There are various functionalised ILs, but hydrophobic ILs
containing
a chiral anion have not yet been reported.
Hydrophobicity should provide various advantages for chiral
ILs.10 The designability of the amino acid as a component of ILs
has the potential to produce hydrophobic and chiral ionic liquids.
In the present study we synthesized hydrophobic ILs by
modification of the amino acid, and we studied their physico-
chemical properties. Hydrophobic ILs are generally obtained when
the cation and/or anion has a long alkyl chain, or the anion is
fluorinated, as in hexafluorophosphate ([PF6]), bis(trifluoro-
methane) sulfonylimide ([Tf2N]), and so on. Introduction of long
alkyl chains to amino acids should provide hydrophobic ILs, but
the additional interaction between alkyl chains through secondary
binding forces (such as the van der Waals force) increased the
melting point of the resulting ILs, and the interaction sometimes
generates liquid-crystalline salts.11 An increase in viscosity was also
found due to the high formula weight of the component ions.
Similarly, hydrophilic groups such as the carboxyl group and
As the cation combined with amino acid derivatives, we chose
both 1-butyl-3-methylimidazolium ([bmim]) and n-tetrabutyl
phosphonium ([TBP]) as shown in Scheme 2. A [bmim] is a
typical cation used to provide many ILs. On the other hand, [TBP]
sometimes generates less viscous and thermally stable AAILs than
conventional imidazolium-based AAILs.6a Furthermore, concen-
trated, pure, and stable [TBP][OH] aqueous solution is commer-
cially available. The [TBP][OH] was a gift from Hokko Chem. Co.
and was used without further purification. In the case of [bmim],
Department of Biotechnology, Tokyo University of Agriculture and
Technology, Koganei, Tokyo 184-8588, Japan.
E-mail: ohnoh@cc.tuat.ac.jp; Fax: +81-42-388-7024;
Tel: +81-42-388-7024
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b606613e
Scheme 1 Preparation of hydrophobic amino acid derivatives.
Chem. Commun., 2006, 3081–3083 | 3081
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length on Tg has been observed in imidazolium based AAILs.6a
The decomposition temperature (Tdecomp) of these ILs was around
250 uC as seen in Table 1. This should be attributable to the
presence of ester bond.
Viscosity was measured using
a cone-plate viscometer
(Brookfield DV-I+). The viscosity of the ILs prepared was affected
mainly by their Tg, and increased according to the alkyl side chain
length, since viscosity at room temperature is governed mainly by
Tg. In general, chiral ILs have higher viscosity, and are mixed in
use with less viscous ILs. A mixture of chiral IL with achiral ionic
liquid would contribute the lower density of the chiral component.
In fact, the ILs prepared were less viscous than some other chiral
ILs.15 The asymmetric imide anion structure and relatively small
formula weight of the anion would generate ILs of less viscosity
than conventional chiral ILs. In general, imide anions such as
[Tf2N], [dca],16 and [TSAC]17 generate less viscous ILs than
carboxylate anion type ILs, and amino acid derived imide anions
should give rise to less viscous ILs than natural amino acid based
ILs. Introduction of imide structure on the amino acid increased
the viscosity of ILs, however.
Scheme 2 Preparation of hydrophobic chiral ILs.
[bmim][OH] aqueous solution was prepared from [bmim][Br] using
anion exchange resin13 (Amberlite IRA400(OH) (SUPELCO)).
However, this [bmim][OH] is not particularly stable, and it should
be used immediately after preparation. These onium hydroxide
aqueous solutions were neutralized with excess amino acid
derivatives having the trifluoromethanesulfonyl group, and the
mixed solutions were then dried to remove water. Since unreacted
fluorinated amino acid derivative is soluble in hexane, the reaction
mixture was washed several times with hexane. The product was
dried in vacuo for at least 2 days at 70 uC, in preparation for DSC
(Seiko Instrument Inc. DSC120) measurement, thermogravimetric
analysis (heating rate: 10 uC min21 under N2 atmosphere, Seiko
Instrument Inc. TG/DTA 220), viscosity measurement, and optical
rotation measurement. The structure of the ILs prepared was
confirmed by electrospray ionization–TOF–mass spectrometry
We confirmed the chirality of anions and corresponding ILs by
optical rotation measurement (JASCO DIP-1000). Trifluoro-
methanesulfonyl amino acid methyl ester was obtained as white
crystals showing chirality (see ESI{). The specific rotation values of
the ILs prepared are also summarized in Table 1. We first
confirmed that neutralization of onium hydroxide with amino
acid, followed by drying at 70 uC for 24 hours, caused no
significant racemization of the corresponding ILs. All rotation
values of these ILs are negative, so that these ILs are levorotatory.
We have confirmed that these ILs maintain their chirality even
after heating at 100 uC for a few hours (data not shown here). The
present procedures involved no asymmetric syntheses and/or
optical resolution, so that these conveniently prepared chiral ILs
have great potential as chiral solvents in various applications. We
obtained chiral ILs simply by neutralization, without special
purification procedures such as chiral separation with column.
To determine the hydrophobicity of the prepared ILs, they were
shaken with an equal volume of water by vortex mixing for 2 min.
Some ILs showed phase separation (Fig. 1). The [bmim] salts were
wholly miscible with water, but [TBP] systems showed two phase
separation. Hydrophobic alkyl chains covering the phosphorus
1
(JEOL JMS-T100LC) and H NMR (JEOL JNM-LA500) (see
note§§2 and ESI{). The amount of water was confirmed at less
than 0.2 wt% by Karl Fischer coulometric titration (Kyoto
Electronics. MKC-510N).
Table 1 summarizes thermal properties of the ILs synthesized.
Except for [TBP][I-Val], all ILs prepared are room temperature
ILs. The melting point (Tm) and glass transition temperature (Tg)
of these synthesized ILs were higher than those of typical
hydrophobic ILs such as [bmim][Tf2N] (Tm 24 uC).3 However,
in the case of ILs with [TBP] cation, the imide anion derived
from amino acid led to a lower melting point than [TBP][Tf2N]
(Tm 86 uC).14 Amino acid derived imide anions gave superior ILs
to [Tf2N] when partnered with phosphonium cations. Since the
asymmetric structure of component ions results in poor packing of
ions, disordering of the component amino acid derived imide
anion would reduce the Tm of ILs. The synthesized ILs also
showed a gradual increase in Tg according to the length of the side
chain of the starting amino acid. A similar effect of the alkyl chain
Table 1 Physico-chemical properties of synthesized amino acid
derived ILs
g/cPa
[a]D
25 b
Tm/uC
Tg/uC
Tdecomp/uC
[bmim][I-Ala]
[bmim][I-Val]
[bmim][I-Leu]
[TBP][I-Ala]
[TBP][I-Val]
[TBP][I-Leu]
ND
ND
ND
ND
61.2
13.8
262.8
242.4
237.5
254.0
269.2
ND
260
253
237
253
277
264
520
3080
4180
700
—
2130
224.6
224.5
222.1
28.4
218.9
216.3
Fig. 1 Mixtures of ILs with water after vortex mixing for 2 minutes. (left
to right): [bmim][I-Ala], [bmim][I-Val], [bmim][I-Leu], [TBP][I-Ala],
[TBP][I-Val], [TBP][I-Leu]. The top of [TBP] systems is aqueous-rich
phase and the bottom is IL-rich phase.
a
b
At 25 uC. c = 1.0 (g per 100 ml MeOH). ND: not detected.
3082 | Chem. Commun., 2006, 3081–3083
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Scientists). This study was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology (Nos. 17205020 and 17073005),
and the 21st Century COE program ‘‘Future Nano-Materials’’.
We appreciated the gift of [TBP][OH] aqueous solution from
Hokko Chem. Co.
Notes and references
{ Characterization of [TBP][I-Ala]. [TBP][I-Ala]: Tetrabutyl-
phosphonium trifluoromethanesulfonylalanine methyl ester salt. 1H
NMR (500 MHz, CDCl3, d/ppm relative to TMS): 0.97(t, J = 7 Hz,
12H), 1.32(d, J = 3.5 Hz, 3H), 1.52(m, J = 11.4 Hz, 16H), 2.28 (m, J =
14.5 Hz, 8H), 3.74(s, 3H), 4.12(q, J = 10.5 Hz, 1H). ESI–TOF–MS: Calcd.
for [C16H36P][C5H7NO4SF3]: [TBP]+: m/z = 259.43; Found: 259.33,
[I-Ala]2: m/z = 234.17; Found: 233.82.
§ Characterization of [I-Ala]. [I-Ala]: N-Trifluoromethanesulfonylalanine
methyl ester. 1H NMR (500 MHz, CDCl3, d/ppm relative to TMS): 1.54 (d,
J = 3.8 Hz, 3H), 3.83 (s, 3H), 4.32 (q, J = 10.8 Hz, 1H), 5.68 (s, 1H). ESI–
TOF–MS: Calcd. for C5H8NO4SF3 [M 2 1 + 2Na]+: m/z = 280.15; Found:
280.06, [M 2 1]2: m/z = 234.17; Found: 233.82. [a] = 226.3 (c = 1.0 g per
100 ml MeOH), Tm = 68.0 uC, Tdecomp. = 119.6 uC.
Fig. 2 Three-phase system of hexane–IL–water. Left: [TBP][I-Leu] with
water, centre: before mixing of hexane–water–[TBP][I-Leu], right: after
mixing of hexane–[TBP][I-Leu]–water. The IL phase was coloured with
Nile Red.
atom may contribute to hydrophobicity. We then analyzed the
water content of the phase-separated IL phase using the Karl
Fischer titration. The water content of the IL-rich phase of the
[TBP][I-Ala] system was 5.1 wt%; [TBP][I-Ala] dissolved slightly in
water. For [TBP][I-Leu] the water content was 2.9 wt%, which
induced distinct separation with an aqueous phase. By comparing
[TBP][I-Ala] with [TBP][I-Leu], we infer that phase separation
behaviour of the prepared ILs is influenced by the alkyl chain
length of the side chain of the amino acids. This clearly shows that
hydrophobicity of the ILs is easily controllable by changing the
side chain of the amino acids used.
1 (a) J. S. Wilkes and M. J. Zaworotko, J. Chem. Soc., Chem. Commun.,
1992, 965; (b) P. Wasserscheid and T. Welton, Ionic Liquids in Synthesis,
Wiley-VCH, Weinheim, Germany, 2003; (c) T. Welton, Chem. Rev.,
1999, 99, 2071.
2 (a) L. Crowhurst, P. R. Mawdsley, J. M. Perez-Arlandis, P. A. Salter
and T. Welton, Phys. Chem. Chem. Phys., 2003, 5, 2790; (b)
J. L. Anderson, J. Ding, T. Welton and D. W. Armstrong, J. Am.
Chem. Soc., 2002, 124, 14247; (c) C. F. Poole, J. Chromatogr., A, 2004,
1037, 49.
3 P. Bonhoˆte, A.-P. Dias, N. Papageorgiou, K. Kalyanasundaram and
M. Gra¨tzel, Inorg. Chem., 1996, 35, 1168.
4 Electrochemical Aspects of Ionic Liquids, ed. H. Ohno, Wiley-
Interscience, New York, 2005.
A three-phase system was constructed by mixing the above two-
phase system (water–[TBP][I-Leu]) with hexane. [TBP][I-Leu]
generally had higher density (1.150 g cm23 at 25 uC) than water;
the bottom phase was rich in ionic liquid (Fig. 2, left). The IL
phase was coloured by Nile Red for easier recognition. With
further addition of hexane to this mixture (Fig. 2, center), the
phase sequence is hexane, water, and [TBP][I-Leu]. However,
vortex mixing of these phases generated an IL phase less dense
than water (Fig. 2, right). The density of [TBP][I-Leu] falls to
0.979 g cm23 by dissolving about 35 wt% hexane. Although some
hydrophobic ILs were also mixed with hexane, these ILs, such as
[bmim][Tf2N] (1.429 g cm23), are denser than water. Use of amino
acids as starting materials readily generates hydrophobic ILs.
Furthermore, the amino acids can themselves have various
functional groups so as to generate novel ILs, and chemical
modification of these functional groups (such as introduction of a
blocking group) has been studied. These advantages make amino
acids highly suitable starting materials in the design of novel
functional ILs.
5 (a) E. D. Bates, R. D. Mayton, I. Ntai and J. H. Davis, Jr., J. Am.
Chem. Soc., 2002, 124, 926; (b) A. E. Visser, R. P. Swatloski,
W. M. Reichert, R. Mayton, S. Sheff, A. Wierzbicki, J. H. Davis, Jr.
and R. D. Rogers, Environ. Sci. Technol., 2002, 36, 2523.
6 (a) K. Fukumoto, M. Yoshizawa and H. Ohno, J. Am. Chem. Soc.,
2005, 127, 2398; (b) J. Kagimoto, K. Fukumoto and H. Ohno, Chem.
Commun., 2006, 2254.
7 (a) N. Gathergood, M. T. Garcia and P. J. Scammells, Green Chem.,
2004, 6, 166; (b) M. T. Garcia, N. Gathergood and P. J. Scammells,
Green Chem., 2005, 7, 9.
8 (a) B. Jastorff, R. Sto¨rmann, J. Ranke, K. Mo¨lter, F. Stock,
B. Oberheitmann, W. Hoffmann, J. Hoffmann, M. Nu¨chter,
B. Ondrushka and J. Filser, Green Chem., 2003, 5, 136; (b) A. C.
/
Roslonkiewicz, J. Pernak, J. K. Feder, A. Ramani, A. J. Robertson and
K. R. Seddon, Green Chem., 2005, 7, 855; (c) C. Pretti, C. Chiappe,
D. Pieraccini, M. Gregori, F. Abramo, G. Monni and L. Intorre, Green
Chem., 2006, 8, 238.
9 (a) W. Bao, Z. Wang and Y. Li, J. Org. Chem., 2003, 68, 591; (b)
H. Clavier, L. Boulanger, N. Audic, L. Toupet, M. Mauduit and
J.-C. Guillemin, Chem. Commun., 2004, 1224; (c) F. Guillen, D. Bre´geon
and J.-C. Plaquevent, Tetrahedron Lett., 2006, 47, 1245.
10 P. J. Dyson and T. J. Geldbach, Metal Catalysed Reactions in Ionic
Liquids, Springer-Verlag, Berlin, 2005.
In conclusion, we have designed a new family of hydrophobic
and chiral anions from amino acids that form unique ILs.
Combined with [TBP] cation, amino acid derivatives yielded
hydrophobic ILs. Although properties such as melting point,
viscosity, and hydrophobicity were not improved over typical
hydrophobic ILs [bmim][Tf2N], these syntheses are the first simple
preparations of hydrophobic ILs having chiral anion. The use of
different amino acids as starting materials allows choice of the
physico-chemical properties of the prepared IL.
11 J. D. Holbrey and K. R. Seddon, J. Chem. Soc., Dalton Trans., 1999,
2133.
12 A. K. Croft, C. J. Easton, K. Kociuba and L. Radom, Tetrahedron:
Asymmetry, 2003, 14, 2919.
13 J. Golding, S. Forsyth, D. R. MacFarlane, M. Forsyth and
G. B. Deacon, Green Chem., 2002, 4, 223.
14 R. E. Del Sesto, C. Corley, A. Robertson and J. S. Wilkes, J. Organomet.
Chem., 2005, 690, 2536.
15 G. Tao, L. He, N. Sun and Y. Kou, Chem. Commun., 2005, 3562.
16 D. R. MacFarlane, J. Golding, S. Forsyth, M. Forsyth and
G. B. Deacon, Chem. Commun., 2001, 1430.
K.F. acknowledges the financial support of the Japan Society
for the Promotion of Science (Research Fellowship for Young
17 H. Matsumoto, H. Kageyama and Y. Miyazaki, Chem. Commun., 2002,
1726.
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Chem. Commun., 2006, 3081–3083 | 3083