LCST-type phase changes of a mixture of water and ionic liquids derived from amino acids

Article abstract of DOI:10.1002/anie.200604402

(Figure Presented) Out of phase: Ionic liquids (ILs) derived from amino acids exhibit phase separation with a lower critical solution temperature after mixing with water (see picture; upper phase water; lower phase IL). The phase-separation temperature of these mixtures depends on the ion structure and water content, and is lowered by an increase in the hydrophobicity of the ionic liquid.

Full text of DOI:10.1002/anie.200604402

Communications
DOI: 10.1002/anie.200604402
Ionic Liquids
LCST-Type Phase Changes of a Mixture of Water and Ionic Liquids
Derived from Amino Acids**
Kenta Fukumoto and Hiroyuki Ohno*
Ionic liquids (ILs)[1] are organic salts designed to melt below
1008C, in particular at room temperature, which have
characteristic properties such as negligible volatility[2] and
nonflammability over a wide temperature range. There is
increasing interest in ILs that have functional groups designed
for specific applications.[3] Many reactions have already been
studied in ILs; most proceed as in ordinary molecular liquids.
Cooperative action of ILs with molecular liquids should also
be significant. The partition coefficients of many molecules in
IL/molecular solvent mixtures have been determined.[4]
Reversible phase control of the mixture is important in
proceeding from the start of the reaction to the separation of
products. Some phase-separation behavior has already been
reported, including pressure-controlled IL/supercritical CO2
mixtures[5] and temperature-driven IL/alcohol[6] and IL-
K3PO4/water systems.[7] Seddon et al. recently reported that
an immiscible pair of ILs mixed upon heating to give a
monophase.[8]
We have previously synthesized ILs from 20 different
amino acids and studied the effect of functional groups of the
side chain on their physicochemical properties.[9] Hydro-
phobic and chiral ILs that are insoluble in water have also
been prepared by chemical modification of the amino acids.[10]
By measuring the solubility of these amino acid derived ILs in
water, we found that a mixture of newly prepared IL and
water exhibited unique phase behavior. The mixture showed
phase separation with a lower critical solution temperature
(LCST). LCST-type phase separation has been found in some
polymer solutions. Conversely, ILs such as [bmim][BF4]
(bmim = 1-butyl-3-methylimidazolium),[11] ionic compounds,
and molecular liquids generally displayed phase separation
with an upper critical solution temperature, because the
solubility of these compounds in water increases with temper-
ature. Few reports exist of LCST-type phase separation of IL/
molecular liquid mixtures.[12] However, the LCST phase
diagram reported was only observed at high and limited IL
content (60–65%). There was no direct demonstration of
clear phase separation above the critical temperature. It is
desirable to arrange similar LCST-type phase separation in
water/IL mixtures, because the partition coefficient of
environmentally effective materials in the water phase is of
great interest; at present there are no reports of LCST-type
phase separation in such a mixture. LCST-type phase
separation with water also offers advantages in the study of
thermosensitive biological compounds, such as enzymes,
peptides, and hormones. In the present study, we synthesized
ILs that exhibit LCST-type phase separation with water. We
discuss the effect of water content and of component-ion
structure on the phase-separation temperature of a mixture
with water.
The amino group on the amino acid was modified using a
synthetic procedure similar to one we have already repor-
ted.[9b,13] N-Trifluoromethanesulfonyl amino acid methyl ester
was synthesized by reaction of trifluoromethanesulfonic
anhydride with amino acid methyl ester (Scheme 1a). Of
Scheme 1. Preparation of N-trifluoromethanesulfonyl amino acids. For
R, see Figure 1.
the natural amino acids, l-valine, l-leucine, l-isoleucine, and
l-phenylalanine were selected as starting materials, as they
have no reactive functional group on the side chain. To
hydrolyze the methyl ester groups, the amino acid derivative
was treated with 1n NaOH solution at 08C for 5 h, and the
sodium ions were removed with proton-exchange resin
(Amberlite IR120(H)). The product was washed with
hexane to give N-trifluoromethanesulfonyl amino acid
(Scheme 1b).
As a counter cation to couple the N-trifluoromethanesul-
fonyl amino acid, we used the tetra-n-butylphosphonium
cation ([P4444]), which provides hydrophobic amino acid
ILs.[10] A tri-n-butyloctylphosphonium cation ([P4448]) was
also used as a more hydrophobic cation than [P4444]. A
solution of [P4444][OH] was donated by Hokko Chem. Co. Ltd.
In the case of [P4448], an aqueous solution of [P4448][OH] was
prepared by passing an aqueous solution of [P4448][Br] through
an anion-exchange resin.[9a,10] These phosphonium hydroxide
aqueous solutions were mixed with a slightly smaller amount
[*] K. Fukumoto, Prof. Dr. H. Ohno
Department of Biotechnology
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
Fax: (+81)42-388-7024
E-mail: ohnoh@cc.tuat.ac.jp
[**] K.F. acknowledges the financial support of the Japan Society for the
Promotion of Science (Research Fellowship for Young Scientists).
This study was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan (17205020 and 17073005), and the 21st Century
COE program of “Future Nano-Materials” in Tokyo University of
Agriculture & Technology. LCST: lower critical solution temperature.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
of trifluoromethanesulfonyl amino acid, and the ILs were
extracted from the mixed solutions with chloroform. After
evaporation, the product (Figure 1) was dried in vacuo for at
least 24 h at 808C. The structure of the resulting ILs was
confirmed by 1H NMR spectroscopy (JEOL JNM-LA500,
JNM-ECX400), ESI time-of-flight (TOF) mass spectrometry
(JEOL JMS-T100LC), and elemental analysis (Elementar
vario EL III; see Experimental Section).
the volume of the IL phase increased gradually (Figure 2a–c)
until a completely miscible state appeared at 228C (Fig-
ure 2d). As is clear from a video, this behavior is a result of
water dissolving in the IL phase as cooling proceeds (see
Supporting Information). The monophase mixture was left
for a few minutes at 228C, but particle phase separation was
not confirmed. This homogeneous mixture demonstrates that
the IL and water are completely miscible below 228C. An
increase in the temperature of the liquid induced phase
separation and generated a cloudy suspension (Figure 2e),
then macroscopic phase separation (Figure 2f). The separate
water and IL phases finally became clear (Figure 2g). The
milky phase can be explained as the formation of emulsions
from the homogeneous mixture, as the solubility of water in
the IL decreases with the increase of temperature. The
sequence of the phase behavior (Figure 2a !g) as the
temperature varies is reversible. Nile Red always dissolved
in the IL phase alone.
The phase-separation temperature can be determined as
the cloud point; we analyzed the effect of the mixing ratio on
phase separation. As all the ILs synthesized in this study
exhibited LCST-type phase behavior with water, the LCST-
type phenomenon does not depend on the specific structure
of the side chain on the anions. Also, amino acid ILs
containing a carboxylic acid protected as the methyl ester[10]
did not exhibit LCST-type phase separation. These results
indicate that free carboxyl groups on hydrophobic amino acid
anions play an important role in LCST-type phase separation.
The phase-separation temperature always varied with the
water content, and the increasing water content in the mixture
lowered the phase-separation temperature (Figure 3). This
trend is consistent with the observation that the ILs dissolve
more water with cooling. The phase-separation temperature
in the phase diagram was monotonic in the water content,
even at 90 wt% water with [P4444][Tf-Phe]. In the high-water-
content region these ILs were not fully dissolved, and
remained solid at room temperature except for [P4448][Tf-
Leu]. In the case of [P4448][Tf-Leu], the phase-separation
temperature reached the freezing point of water (see
Figure 3). Accordingly, further experiments cannot be carried
out with more than 60 wt% water in open conditions.
Figure 1. Structure of the prepared ILs. Tf: trifluoromethanesulfonyl.
The thermal properties of the resulting ILs were deter-
mined by differential scanning calorimetry (DSC; Seiko
Instrument Inc. DSC120). Salts with [P4444] were solid, with
melting points in the range 50–658C (Table 1). [P4444] is known
Table 1: Physicochemical properties of the prepared ILs.
m.p. [8C]
[a][a] [degcm3 gꢀ1 dmꢀ1
]
[P4444][Tf-Val]
[P4444][Tf-Leu]
[P4444][Tf-Ile]
[P4444][Tf-Phe]
[P4448][Tf-Leu]
51
64
51
4.5
9.8
3.6
1.5
7.0
64
ꢀ50[b]
[a] c=1.0 gcmꢀ3 (g/100 mL MeOH). [b] Glass transition temperature.
to provide salts with high melting points even after coupling
with Tf2N (ca. 868C),[14] so these melting points are quite low
for phosphonium salts. It should be possible to lower them by
using asymmetric cations. However, [P4448][Tf-Leu] displayed
no melting point but did have a glass transition temperature,
which reflected a stable supercooling phase. We also mea-
sured the chirality of the resulting ILs by optical rotation
measurement (JASCO DIP-1000). Table 1 summarizes the
specific rotation values of the ILs prepared.
Figure 2shows photographs of a graded series in a two-
phase system (upper phase water; lower phase [P4444][Tf-
Leu]). These mixtures were cooled gradually with stirring,
and then heated after formation of the monophase. The metal
bar penetrating into the vessel was a temperature sensor, and
the IL phase was colored by Nile Red,[15] which was insoluble
in the aqueous phase. Upon cooling of the two-phase system,
Figure 2. Temperature dependence of the phase behavior of a [P4444]-
[Tf-Leu]/water mixture.
Figure 3. Phase-separation temperature versus water content.
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Communications
[Tf-Ile]:
N-Trifluoromethanesulfonylisoleucine:
1H NMR
Similarly, an increase in hydrophobicity of the side chain
(400 MHz, CDCl3, relative to TMS): d = 0.97 (t, J = 7.6 Hz, 3H),
1.06 (d, J = 3.2Hz, 3H), 1.23 (m, J = 22.4 Hz, 1H), 1.47 (m, J =
16.4 Hz, 1H), 2.02 (m, J = 12.6 Hz, 1H), 4.20 (q, J = 7.2Hz, 1H),
5.73 ppm (d, J = 4.8 Hz, 1H); ESI-TOF-MS: m/z calcd for
C7H12NO4SF3 [Mꢀ1]ꢀ: 262.23; found: 262.22; elemental analysis
calcd (%) for C7H12NF3O4S: C 31.94, H 4.59, N 5.32, F 21.65, O 24.31,
S 12.18; found: C 32.14, H 4.88, N 5.18.
caused the phase-separation temperature to fall. As the
solubility of water is less in the more hydrophobic ILs, a lower
IL temperature is needed to dissolve the same amount of
water. The hydrophobicity of the ILs could also be controlled
by changing the structure of the component cation. With a
more hydrophobic cation than [P4444], the phase-separation
temperature of [P4448][Tf-Leu] was about 158C lower than in
the [P4444] system. These results imply that the phase-
separation temperature of the mixture can be controlled by
the side-chain structure on the starting amino acid, by the
alkyl chain length of the cation, and by the water/IL ratio. To
exploit the various separation processes, information is
needed on the phase-separation temperature of the mixture
according to the structure and water content. Introduction of
a functional group, such as a catalyst, on the starting amino
acid side chain would readily provide LCST-type functional-
ized ILs with water.
In summary, we have synthesized ILs that exhibit LCST-
type phase separation with water. The phase-separation
temperature of these mixtures depends reproducibly on the
ion structure and water content. Although the mechanism of
the LCST-type phase behavior of the ILs is not clear, these
ILs could have a great impact on reaction and separation
processes.
[Tf-Phe]: N-Trifluoromethanesulfonylphenylalanine: 1H NMR
(400 MHz, CDCl3, relative to TMS): d = 3.22 (q, J = 8.7 Hz, 2H),
4.58 (m, J = 7.1 Hz, 1H), 5.52(d, J = 4.6 Hz, 1H), 7.18 (q, J = 4.6 Hz,
2H), 7.34 ppm (m, J = 10.5 Hz, 3H); ESI-TOF-MS: m/z calcd for
C10H10NO4SF3 [Mꢀ1]ꢀ: 296.24; found: 296.23; elemental analysis
calcd (%) for C10H10NF3O4S: C 40.41, H 3.39, N 4.71, F 19.17, O 21.53,
S 10.79; found: C 40.40, H 3.48, N 4.54.
Synthesis and characterization of phosphonium-type ILs: A
solution of [P4444][OH] (Hokko Chem. Co.) was used without further
purification. An aqueous solution of [P4448][OH] was prepared by
passing an aqueous solution of [P4448][Br] through anion-exchange
resin (Amberlite IRA400(OH) (SUPELCO)). These phosphonium
hydroxide aqueous solutions were mixed with slightly less trifluoro-
methanesulfonyl amino acids, and the corresponding ILs were
extracted from the mixed solutions with chloroform. After evapo-
ration, the product was dried in vacuo for at least 24 h at 808C.
[P4444][Tf-Val]: Tetra-n-butylphosphonium trifluoromethanesul-
fonyl valine salt: [P4444][Tf-Val] (2.0 g) was obtained from Tf-Val
(1.5 g, 6.0 mmol); 65% yield. 1H NMR (400 MHz, CDCl3, relative to
TMS): d = 0.96 (m, J = 38 Hz, 18H), 1.52(m, J = 11.2 Hz, 16H), 2.25
(m, J = 10.8 Hz, 1H), 2.34 (m, J = 14.4 Hz, 8H), 3.78 ppm (s, 1H);
ESI-TOF-MS: m/z calcd for [C16H36P][C6H9NO4SF3]: positive ion
[P4444]+: 259.43; found: 259.26; negative ion [Tf-Val]ꢀ: 248.20; found:
248.19; elemental analysis calcd (%) for C22H45NF3O4PS: C 52.05, H
8.94, N 2.76, F 11.23, O 12.61, P 6.10, S 10.79; found: C 52.14, H 8.94,
N 2.50; Tdecomp 2748C.
[P4444][Tf-Leu]: Tetra-n-butylphosphonium trifluoromethanesul-
fonyl leucine salt: [P4444][Tf-Leu] (1.4 g) was obtained from Tf-Leu
(1.0 g, 3.8 mmol); 71% yield. 1H NMR (500 MHz, CDCl3, relative to
TMS): d = 1.02(m, J = 53.5 Hz, 18H), 1.52(t, J = 3 Hz, 16H), 1.66 (m,
J = 36.5 Hz, 2H), 1.92 (m, J = 20 Hz, 1H), 2.31 (s, 8H), 3.90 ppm (q,
J = 6 Hz, 1H); ESI-TOF-MS: m/z calcd for [C16H36P][C7H11NO4SF3]:
positive ion [P4444]+: 259.43; found: 259.26; negative ion [Tf-Leu]ꢀ:
262.23; found: 262.22; elemental analysis calcd (%) for
C23H47NF3O4PS: C 52.96, H 9.08, N 2.69, F 10.93, O 12.27, P 5.94, S
6.15; found: C 52.91, H 8.73, N 2.52; Tdecomp 2578C.
[P4444][Tf-Ile]: Tetra-n-butylphosphonium trifluoromethanesul-
fonyl isoleucine salt: [P4444][Tf-Ile] (1.6 g) was obtained from Tf-Ile
(1.0 g, 3.8 mmol); 80% yield. 1H NMR (400 MHz, CDCl3, relative to
TMS): d = 0.89 (t, J = 7.6 Hz, 3H), 0.97 (m, J = 16.4 Hz, 15H), 1.24
(m, J = 13.2Hz, 1H), 1.52(m, J = 2.4 Hz, 17H), 1.92 (m, J = 0.6 Hz,
1H), 2.30 (t, J = 12.8 Hz, 8H), 3.83 ppm (t, J = 0.8 Hz, 1H); ESI-
TOF-MS: m/z calcd for [C16H36P][C7H11NO4SF3]: positive ion [P4444]+:
259.43; found: 259.27; negative ion [Tf-Ile]ꢀ: 262.23; found: 262.22;
elemental analysis calcd (%) for C23H47NF3O4PS: C 52.96, H 9.08, N
2.69, F 10.93, O 12.27, P 5.94, S 6.15; found: C 52.88, H 9.31, N 2.53;
Tdecomp 2678C.
[P4444][Tf-Phe]: Tetra-n-butylphosphonium trifluoromethanesul-
fonyl phenylalanine salt: [P4444][Tf-Phe] (1.3 g) was obtained from Tf-
Phe (1.0 g, 3.4 mmol); 70% yield. 1H NMR (400 MHz, CDCl3,
relative to TMS): d = 0.97 (t, J = 7.2Hz, 12H), 1.49 (m, J = 3.6 Hz,
16H), 2.25 (m, J = 12.8 Hz, 8H), 3.19 (m, J = 21.8 Hz, 2H), 4.17 (t, J =
4.4 Hz, 1H), 7.24 ppm (m, J = 41 Hz, 5H); ESI-TOF-MS: m/z calcd
for [C16H36P][C10H9NO4SF3]: positive ion [P4444]+: 259.43; found:
259.27; negative ion [Tf-Phe]ꢀ: 296.24; found: 296.23; elemental
analysis calcd (%) for C26H45NF3O4PS: C 56.20, H 8.16, N 2.52, F
10.26, O 11.52, P 5.57, S 5.77; found: C 55.99, H 8.20, N 2.39; Tdecomp
2408C.
Experimental Section
Synthesis and characterization of N-trifluoromethanesulfonyl amino
acid: Amino acid was added to methanol, which had been pretreated
with thionyl chloride at 08C, and was stirred overnight. The mixture
was then filtered to remove unreacted amino acid, and the filtrate was
concentrated under reduced pressure (yield 80–90%). The resulting
white solid was suspended in dichloromethane, and bimolar triethyl-
amine was added with stirring. A solution of trifluoromethanesulfonic
anhydride in dichloromethane was added to the mixture under a dry
nitrogen gas atmosphere at ꢀ788C. The mixture was then stirred
overnight at room temperature. The resulting solution was washed
with dilute hydrochloric acid and then with saturated aqueous sodium
chloride. The concentrated dichloromethane solution was shaken
with diethyl ether under reduced pressure. The extract was purified
on silica gel (MeOH/CHCl3 1:5) to provide the corresponding N-
trifluoromethanesulfonyl amino acid methyl ester (ca. 50–60% yield).
To hydrolyze the methyl ester groups, this compound was treated with
1n NaOH solution at 08C for 5 h, and sodium ions were then removed
with proton-exchange resin (Amberlite IR120(H)). The product was
washed with hexane to give N-trifluoromethanesulfonyl amino acid
(50–60% yield).
[Tf-Val]: N-Trifluoromethanesulfonylvaline: 1H NMR (500 MHz,
CDCl3, relative to tetramethylsilane (TMS)): d = 0.97 (d, J = 3.5 Hz,
3H), 1.09 (d, J = 3.5 Hz, 3H), 2.30 (m, J = 16 Hz, 1H), 4.14 (t, J =
2.5 Hz, 1H), 5.68 ppm (d, J = 5.5 Hz, 1H); ESI-TOF-MS: m/z calcd
for C6H10NO4SF3 [Mꢀ1]ꢀ: 248.20; found: 248.19; elemental analysis
calcd (%) for C6H10NF3O4S: C 28.92, H 4.04, N 5.62, F 22.87, O 25.68,
S 12.87; found: C 29.07, H 3.90, N 5.48.
[Tf-Leu]:
N-Trifluoromethanesulfonylleucine:
1H NMR
(500 MHz, CDCl3, relative to TMS): d = 1.00 (q, J = 4.3 Hz, 6H),
1.7 (m, J = 35 Hz, 2H), 1.87 (m, J = 20 Hz, 1H), 4.28 (m, J = 12Hz,
1H), 5.55 ppm (d, J = 4.8 Hz, 1H); ESI-TOF-MS: m/z calcd for
C7H12NO4SF3 [Mꢀ1]ꢀ: 262.23; found: 262.21; elemental analysis
calcd (%) for C7H12NF3O4S: C 31.94, H 4.59, N 5.32, F 21.65, O 24.31,
S 12.18; found: C 31.72, H 4.41, N 5.05.
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[P4448][Tf-Leu]: Tri-n-butyloctylphosphonium trifluoromethane-
sulfonyl leucine salt: [P4448][Tf-Leu] (1.7 g) was obtained from Tf-Leu
(1.0 g, 3.8 mmol); 77% yield. 1H NMR (400 MHz, CDCl3, relative to
TMS): d = 0.94 (m, J = 29.4 Hz, 18H), 1.31 (m, J = 13.2Hz, 8H), 1.52
(m, J = 4 Hz, 17H), 1.68 (m, J = 13.2Hz, 1H), 1.91 (m, J = 13.6 Hz,
1H), 2.37 (m, J = 20.4 Hz, 8H), 3.85 ppm (t, J = 5.6 Hz, 1H); ESI-
TOF-MS: m/z calcd for [C20H44P][C7H11NO4SF3]: positive ion [P4448]+:
315.54; found: 315.31; negative ion [Tf-Leu]ꢀ: 262.23; found: 262.22;
Tdecomp 2598C.
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Keywords: amino acids · chirality · ionic liquids · LCST ·
phase behavior
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