Preparation of novel hydrophobic fluorine-substituted-alkyl sulfate ionic liquids and application as an efficient reaction medium for lipase-catalyzed reaction

Article abstract of DOI:10.1016/j.tetlet.2006.01.017

Various types of differently fluorinated-alkyl sulfate ionic liquids have been prepared; the hydrophobicity was dependent on the content ratio of the fluorine on the alkyl sulfate anion and 2,2,3,3,4,4,5,5-octafluoropentyl sulfate salts showed hydrophobic properties. Melting point and viscosity were also dependent on the fluorine contents of the anionic part, while conductivity was determined by the cationic part and not influenced by the fluorine contents. Efficient lipase-catalyzed transesterification was demonstrated using hydrophobic 1-butyl-3-methylimidazolim 2,2,3,3,4,4,5,5-octafluoropentyl sulfate ([bmim][C5F8]) as solvent.

Full text of DOI:10.1016/j.tetlet.2006.01.017

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1801–1804
Preparation of novel hydrophobic fluorine-substituted-alkyl
sulfate ionic liquids and application as an efficient reaction
medium for lipase-catalyzed reaction
Yasuhiro Tsukada,b Kazuhisa Iwamoto,a Hiroyuki Furutani,b Yuichi Matsushita,a
Yoshikazu Abe,a Kei Matsumoto,a Keishi Monda,a Shuichi Hayase,a
Motoi Kawatsuraa and Toshiyuki Itoha,*
aDepartment of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
bKANEKA CORPORATION, 5-1-1 Torikai-nishi, Settsu, Osaka 566-0072, Japan
Received 21 November 2005; revised 5 January 2006; accepted 6 January 2006
Available online 24 January 2006
Abstract—Various types of differently fluorinated-alkyl sulfate ionic liquids have been prepared; the hydrophobicity was dependent
on the content ratio of the fluorine on the alkyl sulfate anion and 2,2,3,3,4,4,5,5-octafluoropentyl sulfate salts showed hydrophobic
properties. Melting point and viscosity were also dependent on the fluorine contents of the anionic part, while conductivity was
determined by the cationic part and not influenced by the fluorine contents. Efficient lipase-catalyzed transesterification was dem-
onstrated using hydrophobic 1-butyl-3-methylimidazolim 2,2,3,3,4,4,5,5-octafluoropentyl sulfate ([bmim][C5F8]) as solvent.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Room temperature ionic liquids (ILs) are a new class of
solvents and have attracted growing interest recently
because of their unique physical and chemical proper-
ties; they are non-volatile, non-flammable, have low toxi-
city, and good solubility for many organic and
inorganic materials.1 We have been investigating enzy-
matic2 or chemical3 reactions in an ionic liquid solvent
system. It is acknowledged that the key point for realiz-
ing successful reactions is finding an appropriate combi-
nation of the cationic and anionic parts of this solvent.1
Although there are many reports concerning enhanced
enantioselectivity or regioselectivity of lipase-catalyzed
reaction in an ionic liquid solvent system,1,4 it has also
been reported that some ionic liquids significantly inhib-
ited the lipase-catalyzed reaction.1,2a,5–7 It is known that
the anionic part of the ionic liquids has a strong impact
on the activity of lipases.1c,2a,4–7 Among the ionic liquids
solvent for lipase-catalyzed reactions, the results of reac-
tions in imidazolium alkyl sulfates are interesting.2d,5,6
We established that a lipase worked well as catalyst
for transesterification of secondary alcohols in 1-butyl-
3-methylimidazolium ([bmim]) methoxyethoxymethyl
sulfate or phenoxyethoxymethyl sulfate, while a very
poor reaction rate was obtained for the reactions in a
[bmim][MeSO4] or [bmim][BuSO4] solvent system.2d,5
Sheldon and co-workers suggested that ethyl sulfate
anion interacted with the lipase protein and caused
deactivation of the lipase based on the results of a FT-
IR experiment of the lipase protein.6 Hydrophobic ionic
liquids generally work as a good solvent for lipase-cata-
lyzed reaction,1–7 and imidazolium alkyl sulfates are
very hydrophilic with strong hygroscopic property.2d
Therefore, we expected that improved reaction might
be obtained if we conducted the lipase-catalyzed trans-
esterification in more highly hydrophobic imidazolium
alkyl sulfate ionic liquids. In this letter, we report that
modification of the alkyl part of the sulfate by fluorine
atom made it possible to prepare hydrophobic alkyl sul-
fate ionic liquids. Efficient lipase-catalyzed transesterifi-
cation was accomplished using a fluorinated-alkyl
sulfate imidazolium as solvent.
First, we prepared [bmim] salts with three types of alkyl
sulfates: pentyl sulfate ([C5F0]), 4,4,5,5,5-pentafluoro-
pentyl sulfate ([C5F5]), or 2,2,3,3,4,4,5,5-octafluoropen-
tyl sulfate ([C5F8]) following the method that we
Keywords: Novel ionic liquid; Lipase; Fluorine; Enantioselective
transesterification.
*
Corresponding author. Tel./fax: +81 857 31 5259; e-mail: titoh@
chem.tottori-u.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.017

1802
Y. Tsukada et al. / Tetrahedron Letters 47 (2006) 1801–1804
Table 1. Physical properties of ionic liquids containing fluorinated-alkyl sulfate
IL
Cation
Anion
Hydrophobic propertya
Mp/ꢁC
Viscosity/P
Conductivity/S cmꢀ1
[bmim][C5F0]
[bmim][C5F5]
[bmim][C5F8]
n-C5H11OSOꢁ3
j
h
s
ꢀ17.0
ꢀ15.1
ꢀ61.2
2.4
2.5
1.7
8.3 · 10ꢀ4
6.3 · 10ꢀ4
8.5 · 10ꢀ4
Bu
Me
N
CF3CF2ðCH2Þ3OSO3ꢁ
N
CHF2ðCF2Þ3CH2OSO3ꢁ
[emim][C5F5]
[emim][C5F8]
CF3CF2ðCH2Þ3OSO3ꢁ
CHF2ðCF2Þ3CH2OSO3ꢁ
h
s
—
ꢀ16.1
—
0.54
—
Et
Me
N
N
N
2.4 · 10ꢀ3
CF3CF2ðCH2Þ3OSO3ꢁ
h
s
12.6
32
8.4
1.0 · 10ꢀ4
2.7 · 10ꢀ4
Me
[bdmim][C5F5]
[bdmim][C5F8]
Bu
Me
CHF2ðCF2Þ3CH2OSO3ꢁ
ꢀ14.2
N
[tea][C2F3]
[tea][C3F4]
[tea][C5F8]
CF3CH2OSOꢁ3
CHF2CF2CH2OSOꢁ3
CHF2ðCF2Þ3CH2OSO3ꢁ
j
h
s
5.0
ꢀ9.0
13
8.2
9.1
3.5 · 10ꢀ4
2.8 · 10ꢀ4
2.6 · 10ꢀ4
Et4Nꢂ
ꢀ13.0
[tba][C2F3]
[tba][C3F4]
[tba][C5F8]
CF3CH2OSOꢁ3
CHF2CF2CH2OSOꢁ3
CHF2ðCF2Þ3CH2OSO3ꢁ
j
h
s
76–83
ꢀ4.0
ꢀ8.0
—
5.8
1.8
—
n-Bu4Nꢂ
4.6 · 10ꢀ5
3.6 · 10ꢀ5
[oma][C2F3]
[oma][C3F4]
[oma][C5F8]
CF3CH2OSOꢁ3
CHF2CF2CH2OSOꢁ3
CHF2ðCF2Þ3CH2OSO3ꢁ
j
h
s
4.0
ꢀ5.0
ꢀ2.0
14.2
6.9
6.5
4.4 · 10ꢀ6
2.8 · 10ꢀ5
2.2 · 10ꢀ5
Me
(n-C8H17)3N
Et
[dep][C5F8]
[epy][C5F8]
[bpy][C5F8]
CHF2ðCF2Þ3CH2OSO3ꢁ
CHF2ðCF2Þ3CH2OSO3ꢁ
CHF2ðCF2Þ3CH2OSO3ꢁ
s
s
s
ꢀ7.0
ꢀ11.0
3.1
6.8
2.5
19
2.8 · 10ꢀ5
2.8 · 10ꢀ4
2.2 · 10ꢀ4
N
HN
Et
Et N
n-Bu N
s: Hydrophobic, h: half hydrophobic, j: hydrophilic.
a Hydrophobic property was estimated by a simple test: a 1:1 (v/v) mixture of IL with water was vigorously shaken and allowed to stand for 5 min.
Hydrophobic IL: a 1 to 1 (v/v) biphasic layer was formed. Hydrophilic IL: it was completely dissolved in water and no biphasic layer was obtained.
Half hydrophobic IL: a biphasic layer was obtained but IL:water = <1:>1 (v/v).
reported earlier.2d As can be seen in Table 1,
[bmim][C5F8] showed the lowest melting point and very
hydrophobic property. We evaluated the hydrophobic-
ity of the salts by a simple test: 1:1 (v/v) mixture of
the alkyl sulfate salt and water was vigorously shaken
and allowed to stand for 5 min. Hydrophobic ionic
liquid formed a biphasic layer, while a hydrophilic liquid
dissolved in water: a 1:1 biphasic layer was obtained for
[bmim][C5F8] (Fig. 1, left), while [bmim][C5F0] was
completely dissolved in the water (Fig. 1, right), and
[bmim][C5F5] showed a half hydrophobic property
(Fig. 1, center). Highly fluorinated-alkyl sulfate salts
had low viscous property. On the other hand, the con-
ductivity was independent of the fluorine contents on
the alkyl part of the sulfate anion. Some typical physical
properties of 19 types of alkyl sulfates ionic liquids are
summarized in Table 1.
Among imidazolium salts, [emim][C5F8] showed the
least viscosity and the highest was recorded for
[bdmim][C5F5]. Presence of the methyl group on the
2-position of the imidazolium ring caused an elevated
melting point and increased viscosity. Combination of
[C5F8] anion with three types of alkylammonium
cations, triethylammonium (tea), tributylammonium
(tba), and tris-n-octyl-methylammonium (oma), gave
hydrophobic salts. [C5F8] salts with N,N0-diethylpyper-
izinium (dep), N-ethyl (epy)-, and N-butylpyridinium
(bpy) cations again showed a highly hydrophobic prop-
erty. It was thus found that the hydrophobic property of
these solvents was dependent on the content ratio of the
fluorine atom on the alkyl sulfate part.
We next focused our attention on the application of
alkyl sulfate imidazolium salts as solvent for lipase-
catalyzed reaction (Eq. 1). Lipase PS-catalyzed
transesterification for three different substrates,
1-phenylethanol (1a), 4-phenyl-3-buten-2-ol (1b), and
3-hydroxypentanenitrile (1c), using vinyl acetate as acyl
donor was demonstrated and the results are shown in
Figure 1. Hydrophobicity test of three types of ionic liquids.

Y. Tsukada et al. / Tetrahedron Letters 47 (2006) 1801–1804
Table 2. Lipase PS-catalyzed transesterification in different types of alkyl sulfate IL
1803
OAc
O
R1 R2
( )-2
R
O
OH
R2
( )-1
PS
1.5 eq.
R1
ð1Þ
OH
Solvent. 35 C
˚
R1 R2
(S)-1
Entry
Substrate
Solvent
Time (h)
% ee of (R)-2a (% yield)b
% ee of (S)-1a (% yield)b
% conv.c
Ec
1
2
3
4
5
6
7
Toluene
i-Pr2O
27
24
168
120
24
99 (31)
73 (37)
99 (16)
99 (18)
— (0)
76 (40)
42 (62)
24 (77)
27 (69)
0 (91)
43
37
19
21
0
>200
10
>200
>200
—
OH
[bmim][PF4]
[bmim][BF4]
[bmim][EtSO4]
[bmim][C5F0]
[bmim][C5F8]
H3C
1a
Ph
49
26
90 (7)
98 (25)
18 (68)
31 (68)
16
24
23
150
OH
8
9
[bmim][C5F0]
[bmim][C5F8]
24
48
99 (3)
>99 (31)
7 (82)
69 (33)
7
25
>200
>200
H3C
H3C
Ph
1b
OH
CN
10
11
[bmim][C5F0]
[bmim][C5F8]
16
11
72 (12)
92 (30)
72 (10)
17 (50)
13
16
7
28
1c
a Determined by HPLC (Chiralcel OJ-H, hexane–i-PrOH = 9:1).
b Isolated yield.
c Calculated by % ee of 2 (eep) and % ee of 3 (ees). E = ln[(1ꢀc)(1+eep)]/ln[(1ꢀc)(1ꢀeep)], here c means conv. which was calculated by the following
formula: c = eep/(eep+ees). See Ref. 8.
Table 2. We initially tested the solvent effect using
1-phenylethanol (1a) as substrate; toluene gave the best
results (entry 1) and [bmim][C5F8] was next among the
five solvents tested; the desired (R)-2a was obtained in
25% yield with 98% ee when the reaction was carried
out using [bmim][C5F8] solvent (entry 7). On the con-
trary, the reaction proceeded very slowly in a conven-
tional ionic liquid [bmim][PF6] (entry 3) or
[bmim][BF4] (entry 4), and no reaction took place if
the reaction was carried out in [bmim][EtSO4] (entry
5). Further, only 7% of (R)-2a with 90% ee was obtained
by the reaction using [bmim][C5F0] solvent (entry 6). It
was thus found that [bmim][C5F8] was the best solvent
among the tested five ionic liquids (entries 3–7). It
should be emphasized that [bmim][C5F8] is non-volatile
and non-flammable solvent. Use of [bmim][C5F8] as sol-
vent makes it possible to realize a very safety reaction
process instead of traditional flammable organic solvent
such as toluene.
We next demonstrated the recycling use of enzyme in the
[bmim][C5F8] solvent system using 1b as substrate (Eq.
2 and Table 3). As shown in Table 3, recycling of the
enzyme was indeed possible in our novel ionic liquid
solvent system, though both the reaction rate and
enantioselectivity gradually dropped with repetition of
the reaction process in the system when lipase PS was
used as catalyst (entries 1–5).2
For the recycling of lipase, 1-butyl-2,3-dimethylimidazo-
lium tetrafluoroborate ([bdmim][BF4]) solvent gave bet-
ter results than did [bmim][BF4].2e However, it was found
that the transesterification of 1b using [bdmim][C5F8]
solvent proceeded very slowly due to the highly viscous
nature of the solvent. We recently reported that 1-butyl-
2,3-dimethylimidazolium cetyl-PEG10-sulfate (IL1)
coated lipase PS (IL1-PS) showed excellent reactivity.2g
IL1-PS worked very efficiently in the [bmim][C5F8] sol-
vent system. To our delight, (R)-2b was obtained with
excellent enantioselectivity using IL-1-PS and, five repe-
titions of this process showed no significant drop of the
reaction rate (entries 6–10). We thus succeeded to dem-
onstrate the recycling use of lipase in [bmim][C5F8]
using IL-1-PS as catalyst.
Better results were again recorded for the reactions of 1b
and 1c using [bmim][C5F8] solvent (entries 7 and 9)
compared to those in the [bmim][C5F0] solvent system
(entries 6 and 8). It should be noted that a remarkable
enhancement of enantioselectivity was obtained when
1c was subjected to the lipase-catalyzed reaction switch-
ing the solvent from [bmim][C5F0] (entry 8) to
[bmim][C5F8] (entry 9). It has thus been confirmed that
1-butyl-3-methylimidazolium 2,2,3,3,4,4,5,5-octafluoro-
pentyl sulfate is an appropriate solvent to achieve
lipase-catalyzed transesterification.
In conclusion, we demonstrated a successful example of
lipase-catalyzed enantioselective transesterification in a
novel alkyl sulfate imidazolium solvent system. It was
possible to use the enzyme repeatedly in this system, par-
ticularly, when IL-1-PS was used as catalyst. Since the
starting material of 2,2,3,3,4,4,5,5-octafluoropentanol

1804
Y. Tsukada et al. / Tetrahedron Letters 47 (2006) 1801–1804
Table 3. Lipase PS-catalyzed transesterification in different types of alkyl sulfate IL
OAc
O
H3C
H3C
Ph
Ph
OH
O
( )-2b
R
Lipase
1.5 eq.
ð2Þ
H3C
Ph
OH
1b
[bmim][C5F8], 35 C
˚
( )-1b
S
Entry
Run
Lipase
Time (h)
% ee of (R)-2ba (% yield)b
% ee of (S)-1ba (% yield)b
% conv.c
Ec
1
2
3
4
5
6
7
8
9
10
1st
PS
PS
PS
PS
24
24
24
24
98 (13)
96 (22)
93 (10)
93 (6)
25 (87)
16 (77)
10 (67)
9 (75)
20
14
10
9
148
62
31
31
16
165
65
72
87
54
2nd
3rd
4th
5th
1st
2nd
3rd
4th
5th
PS
24
88 (5)
5 (60)
5
IL1-PS
IL1-PS
IL1-PS
IL1-PS
IL1-PS
2.5
4.5
6.0
8.0
13
98 (32)
96 (22)
96 (30)
97 (20)
97 (18)
51 (62)
29 (66)
39 (61)
29 (77)
23 (78)
34
23
29
23
19
a Isolated yield.
b The enantiomeric excess was determined by HPLC analysis using OJ-H (/ 4.6 mm · 250 mm, hexane–i-PrOH = 9:1, 35 ꢁC).
c See Ref. 8.
Me
O
OS
O
Bu
Me
O
N
N
O
10n-C16H33
IL1
2003, 5, 494–496; (g) Itoh, T.; Han, S.; Matsushita, Y.;
Hayase, S. Green Chem. 2004, 6, 437–439.
is not expensive, we believe this ionic liquid might
become a useful solvent for various types of reactions.
Further investigation of the optimization of the combi-
nation of imidazolium cation and alkyl sulfate anion will
make it even more beneficial.
3. (a) Ohara, H.; Kiyokane, H.; Itoh, T. Tetrahedron. Lett.
2002, 43, 3041–3044; (b) Itoh, T.; Kawai, K.; Hayase, S.;
Ohara, H. Tetrahedron Lett. 2003, 44, 4081–4084; (c) Itoh,
T.; Uehara, H.; Kawai, K.; Hayase, S.; Ohara, H.; Oyama,
M. In Analytical Mechanistic and Synthetic Organic Elec-
trochemistry—6th International M. Baizer Award Sympo-
sium in Honor of Dennis H. Evans and Masao Tokuda;
Lessard, J., Hapiot, P., Nishiguchi, I., Eds.; The Electro-
chemical Society: USA, 2004; pp 9–12.
4. For several recent examples, see: (a) Xin, J.-Y.; Zhao, Y.-J.;
Shi, Y.-G.; Xia, C.-G.; Li, S.-B. World J. Microbiol.
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Acknowledgments
This research was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
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