Synthesis of chiral ionic liquids from natural amino acids

Article abstract of DOI:10.1021/jo020503i

For the first time, chiral imidazolium ionic liquids containing one chiral carbon (10a-c) were synthesized from the natural amino acids by a simple and straight-forward procedure. The characteristics of the chiral ILs are very similar to the popular ionic liquids.

Full text of DOI:10.1021/jo020503i

SCHEME 1
Syn th esis of Ch ir a l Ion ic Liqu id s fr om
Na tu r a l Am in o Acid s
Weiliang Bao,* Zhiming Wang, and Yuxia Li
Zhejiang University, Xi Xi Campus, Department of
Chemistry, Hangzhou, Zhejiang 310028, P. R. China
wbao@mail.hz.zj.cn
Received J uly 29, 2002
Abstr a ct: For the first time, chiral imidazolium ionic
liquids containing one chiral carbon (10a -c) were synthe-
sized from the natural amino acids by a simple and straight-
forward procedure. The characteristics of the chiral ILs are
very similar to the popular ionic liquids.
of optically active substrates and/or reagents, chiral
catalysts, enzymes or chiral solvents.15 Now that the
room-temperature ionic liquids have gained more and
more popularity, synthesis and characterization of chiral
IL are underway. Some of the chiral anions as sodium
salts are readily available. For example, Seddon et al.
investigated Diels-Alder reactions in lactate ILs.16 Howar-
th and co-workers described the use of chiral imidazolium
cations (1) in Diels-Alder reactions (Scheme 1).17 How-
ever, the synthesis of these systems required an expen-
sive chiral alkylating agent; furthermore, two symmetri-
cal chiral centers may not be favorable to chiral induce-
ment. Wasserscheid and co-workers synthesized three
different groups of chiral ionic liquids (2-4).18 However,
under acidic conditions, the oxazoline ring of 2 has lower
stability than the imidazole ring, and 3 and 4 are not
very similar to the popular ionic liquids encompassing
imidazolium cations, which are favorable species for
investigation because of their facile and inexpensive
preparation, their air and water stability, their wide
liquids range, and their relatively favorable viscosity and
density characteristics.19,20 Chiral imidazolium ionic liq-
uids with one chiral center have not been reported until
now.
One of the prime concerns of industry and academia
is the search for replacements to the environmentally
damaging solvents used on a large scale, especially those
that are volatile and difficult to contain. In the recent
years, considerable attention has been focused on the use
of the room-temperature ionic liquids (RTIL) as new clean
media. These solvents possess a number of interesting
properties, such as lack of significant vapor pressure, ease
of reuse, absence of flammability, and tolerance for large
temperature variations. One of the main expected ap-
plications of ionic liquids is to replace volatile organic
solvents traditionally used in industry. There are many
reports concerning the applications of ionic liquids in
organic reactions, such as Friedel-Crafts reactions,1,2
Diels-Alder reactions,3-5 Heck Reactions,6,7 Pechmann
condensations,8 Biginelli reactions,9 and Beckmann
rearrangements.10-11 There has been also a great deal of
interest in the application of the ionic liquids as novel
biphasic catalysts,12 extraction solvents,13 and stationary
phase for chromatography.14
Asymmetric synthesis is one of the most important
areas in organic chemistry, biochemistry, and pharma-
cology. Usually, asymmetric induction is achieved by use
* To whom correspondence should be addressed.
(1) Adams, C. J .; Earle, M. J .; Roberts, G.; Seddon, K. R. Chem.
Commun. 1998, 2097.
(2) Stark, A.; Maclean, B. L.; Singer, R. D. J . Chem. Soc., Dalton
Trans. 1999, 63.
(3) Fischer, T.; Sethi, A.; Welton, T.; Woolf, J . Tetrahedron Lett.
1999, 40, 793.
(4) Lee, C. W. Tetrahedron Lett. 1999, 40, 2461.
(5) Ludley, P.; Karodia, N. Tetrahedron Lett. 2001,42, 2011.
(6) Carmichael, A. J .; Earle, M. J .; Holbrey, J . D.; McCormac, P. B.;
Seddon, K. R. Org. Lett. 1999, 1, 997.
Herein, we report for the first time the synthesis
of chiral imidazolium ionic liquids (10a -c) derived
from natural amino acids. First, we used the chiral amine
as the starting material. Because the aromatic chiral
amine is easilier resoluted than the aliphatic chiral
amine, we chose the R-phenylethylamine as the starting
substrate. We synthesized D-1-ethyl-2-(R-phenylethyl)-
imidazolium tetrafluoroborate, 5, according to the route
(7) Calo`, V.; Nacci, A.; Lopez, L.; Mannarini, N. Tetrahedron Lett.
2000, 41, 8973.
(8) Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett.
2001, 42, 9285.
(9) Peng, J .; Deng, Y. Tetrahedron Lett. 2001, 42, 5917.
(10) Ren, R. X.; Zueva, L. D.; Ou, W. Tetrahedron Lett. 2001, 42,
8441.
(11) Peng, J .; Deng, Y. Tetrahedron Lett. 2001, 42, 403.
(12) Aqueous-Phase Organometallic Catalysis: Concepts and Ap-
plications; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim,
1998.
(13) Huddleston, J . G.; Willauer, H. D.; Swatloski, R. P.; Visser, A.
E.; Rogers, R. D. Chem. Commun. 1998, 1765.
(14) Armstrong, D. W.; He, L.; Lin, Y. S. Anal. Chem. 1999, 71, 3873.
(15) March, J . Advanced Organic Chemistry; McGraw-Hill Book
Co.: New York, 1977; pp 106-108.
(16) Earle, M. J .; McCormac, P. B.; Seddon, K. R. Green Chem. 1999,
1, 23.
(17) Howarth, J .; Hanlon, K.; Fayne, D.; McCormac, P. Tetrahedron
Lett. 1997, 38, 3097.
(18) Wasserscheid, P.; Bo¨smann, A.; Bolm, C. Chem. Commun. 2002,
200.
(19) Wilkes, J . S.; Zaworotko, M. J . J . Chem. Soc., Chem. Commun.
1992, 965.
(20) Fuller, J .; Carlin, R. T.; DeLong, H. C.; Haworth, D. J . Chem.
Soc., Chem. Commun. 1994, 299.
10.1021/jo020503i CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/17/2002
J . Org. Chem. 2003, 68, 591-593
591

SCHEME 2
SCHEME 3
of Scheme 2.21-23 Unfortunately, its melting point is
about 90 °C, and this is not ideal for the chiral induce-
ment, for chiral inducement in many asymmetric reac-
tions at lower reaction temperatures is better than at
higher ones. In addition, optical purity of R-phenylethy-
lamine is not ideal by resolution(ee 95%). Thus, our
studies have focused on the natural amino acids, which
are optically pure and commercially available. We used
L-alanine, L-valine, and L-leucine as the starting materi-
als, which are not very expensive.
In conclusion, we could demonstrate that chiral imi-
dazolium ILs with one chiral center can readily be
prepared from the natural amino acids. Comparing with
the criteria proposed by Wasserscheid18 (easy preparation
by direct synthesis in enantiopure form; melting point
<80 °C; thermal stability up to 100 °C; good chemical
stability vs water and common organic substrates and
relatively low viscosity), our chiral ILs are more satis-
factorily meet it. Furthermore, there are other merits in
this synthesis: (a) the characterization of the chiral ILs
(mp 5-16 °C) are very similar to the popular ionic liquids
encompassing imidazolium cations; (b) good thermal
stability (do not decompose up to 180 °C); (c) the starting
materials are commercially available and synthetic pro-
cedures are simple and straightforward.
There are two ways to obtain imidazolium rings from
amino acids. Amino acids can be first reduced to amino
alcohols and the amino alcohols then condensed with
aldehydes to form imidazoline rings. However, the hy-
droxy group may interfere with the condensation of
amino group with aldehydes. So we chose the second
route, that is, to allow the amino acids to condense with
aldehydes to form imidazole rings under basic conditions.
We put amino acids, formaldehyde, glyoxal, and aqueous
ammonia together and regulated the pH with NaOH
solution, and the crude products, sodium L-2-(1-imida-
zolyl)alkanoic acids (7), were obtained.21 The ethyl acetic
esters (8) were prepared by refluxing 7 in anhydrous
ethyl alcohol saturated with dry hydrogen chloride ac-
cording to known procedures.24 The yields of the above
two steps were 65-79%. The alcohols (9) was prepared
by the reduction of 8 using LiAlH4 in anhydrous Et2O
under reflux (yield 57-60%).25 Finally, the objective
products (10) were obtained by the substitution reaction
of 9 and bromoethane in CH3CCl3.22 The yields of the
reaction were good (80-82%). Thus, the chiral ionic
liquids (10) were prepared in four steps from optically
pure amino acids (6) in 30-33% overall yields (Scheme
3). The chiral ionic liquids are miscible with water,
methanol, acetone, and other strong polar organic sol-
vents and immiscible with ether, 1,1,1-trichloroethane,
and other weakly polar organic solvents.
Exp er im en ta l Section
Gen er a l Meth od s. All reagents and solvents were pure
analytical grade materials purchased from commercial sources
and were used without further purification, if not stated
otherwise. Et2O was distilled from sodium benzophenone ketyl
prior to used. Ethyl alcohol was purified by standard procedure.
All melting points are uncorrected. The NMR spectra were
recorded in CDCl3 on a 400 MHz instrument with TMS as
internal standard. IR spectra were taken as KBr plates. TLC
was carried out with 0.2 mm thick silica gel plates (GF254).
Visualization was accomplished by UV light or I2 staining. The
columns were handpacked with silica gel 60 (200-300). All
reactions were carried out under atmosphere, if not stated
otherwise. The products were further purified by column chro-
matography.
L-Eth yl 2-(1-Im id a zolyl) p r op a n oa te (8a ).26 Formaldehyde
water solution (36%, 16.7 g) and glyoxal water solution (32%,
36.2 g) were added to a 250 mL, three-necked flask provided
with a stirrer and reflux condenser. While the mixture was
heated at 50 °C with stirring, a mixture of alanine (6a ) (17.8 g,
0.2 mol), ammonia solution (28%, 12.1 g), and sodium hydroxide
solution (10%, 80 g) was added in small portions during 0.5 h.
After the mixture was stirred for an additional 4 h at 50 °C, the
water was removed under reduced pressure. The residue was
absolutely dried in a vacuum desiccator with P2O5. The crude
product, sodium l-2-(1-imidazolyl)propanoic acid (7a ), was ob-
tained.21 L-Ethyl 2-(1-imidazolyl)propanoate (8a ) was prepared
by refluxing 7a in anhydrous ethyl alcohol saturated with dry
hydrogen chloride. After the reaction was complete, excess
hydrogen chloride and alcohol were removed under reduced
pressure.24 Saturated Na2CO3 solution was added to the residue
until pH 8-9. The resultant product was extracted with ethyl
acetate and dried with Na2SO4. The product was further purified
(21) Hofmann, K. The Chemistry of Heterocyclic Compounds: Imi-
dazole and Its Derivatives Part; Interscience Publisher: Inc.: New
York, 1956; p 33.
(22) Bonhote, P.; Dias, A. P.; Papageoriou, N. Inorg. Chem. 1996,
35, 1168.
(23) Fuller, J .; Carlin, R. T.; Osteryoung, R. A. J . Electrochem. Soc.
1997, 144, 3881.
(24) Alexander, P. T. E.; Frank, L. P. J . Chem. Soc. 1932, 1806.
(25) J noes, R. G.; Mclaughlin, K. C. J . Am. Chem. Soc. 1949, 71,
2444.
592 J . Org. Chem., Vol. 68, No. 2, 2003

by column chromatography (1:4 petroleum ether/ethyl acetate):
3.71 (m, 1H), 3.88-3.90 (m, 1H), 4.46 (br, OH), 6.92 (m, 2H),
7.37 (s, 1H); 13C NMR δ 19.22, 19.88, 29.96, 62.76, 67.04, 118.05,
128.13, 136.73; IR 3113, 2965, 2876, 1598 cm-1. Anal. Calcd for
C8H14N2O: C, 62.31; H, 9.15; N, 18.17. Found: C, 62.12; H, 9.36;
N, 18.31.
yield 24 g; 70% (two steps overall); oil (bp 122-123/7 mmHg);
[R]25 ) +8.8 (c 2.0, CH3OH); 1H NMR δ 1.24-1.28 (t, J ) 7.14
D
Hz, 3H), 1.73-1.75 (d, J ) 7.30 Hz, 3H), 4.17-4.23 (q, J ) 7.12
Hz, 2H), 4.85-4.90 (q, 7.29 Hz, 1H), 7.03 (s, 1H), 7.07 (s, 1H),
7.59 (s, 1H); 13C NMR δ 13.41, 17.88, 54.48, 61.42, 117.33,
128.76, 135.87, 169.55; IR 3386, 3114, 2986, 1742 cm-1. Anal.
Calcd for C8H12N2O2: C, 57.13; H, 7.19; N, 16.66; Found: C,
57.36; H, 7.31; N,16.46.
L-1-Eth yl-3-(1′-h yd r oxy-3′-m eth yl-2′-bu ta n yl)im id a zoli-
u m Br om id e (10b). This compound was prepared by a proce-
dure similar to that for the preparation of 10a and was further
purified by column chromatography (1:5 CH3OH/ethyl acetate):
yield 48 g, y82%; mp 11-12 °C; [R]25D) -10.0 (c 2.0%, CH3OH);
1H NMR δ 0.82-0.84 (d, J ) 6.68 Hz, 3H), 1.06-1.08 (d, J )
6.65 Hz, 3H), 1.58-1.62 (t, J ) 7.35 Hz, 3H), 2.21-2.28 (m, 1H),
3.75 (br, OH), 3.95-4.02 (m, 2H), 4.29-4.34 (m, 1H), 4.34-4.42
(m, 2H), 7.54 (m, 2H), 9.72 (s, 1H); 13C NMR δ 15.42, 19.35,
19.37, 29.68, 45.28, 61.08, 69.47, 121.37, 122.01, 135.88; IR 3356,
L-2-(1-Im id a zolyl)p r op a n ol (9a ).26 Lithium aluminum hy-
dride (11.4 g) was added to 300 mL of anhydrous ether in a 500
mL three-necked flask with a stirrer and reflux condenser. With
stirring, 33.6 g of 8a was added in small portions during 1 h.25
After the mixture was stirred for 1 h at room temperature, more
lithium aluminum hydride (11.4 g) was added. The mixture was
stirred for an additional 2 h, and then 70 mL of water was very
carefully added dropwise. The resulting suspension of white
granular solid in ether was filtered. The solid was suspended in
methanol, and the mixture was saturated with carbon dioxide
under reflux for 1 h and then filtered. The combined ether and
methanol filtrates were evaporated to dryness, and the resultant
product was further purified by column chromatography (1:4,
3134, 3080, 2968, 2878, 1637, 1560 cm-1. Anal. Calcd for C10H19
-
BrN2O: C, 45.64; H, 7.28; N, 10.64. Found: C, 45.55; H, 7.43;
N, 10.44.
L-Eth yl 2-(1-Im id a zolyl)-4-m eth ylp en ta n oa te (8c). This
compound was prepared by a procedure similar to that for the
preparation of 8a and was further purified by column chroma-
tography (1:1 petroleum ether/ethyl acetate): yield 28 g, 65%
(two steps overall); oil (bp 144-145 °C/7 mmHg); [R]25D) +4.4
(c 2.0%, CH3OH); 1H NMR δ 0.92-0.93 (d, J ) 6.73 Hz, 3H),
0.94-0.95 (d, J ) 6.66 Hz, 3H), 1.25-1.29 (t, J ) 7.10 Hz, 3H),
1.35-1.45 (m, 1H), 1.94-1.97 (t, J ) 7.51 Hz, 2H), 4.18-4.23
(q, J ) 7.12 Hz, 2H), 4.76-4.80 (t, J ) 7.86 Hz, 1H), 7.06 (s,
1H), 7.11 (s, 1H), 7.68 (s, 1H); 13C NMR 14.03, 21.46, 22.63,
24.54, 41.53, 58.45, 62.06, 118.06, 128.59, 136.73, 170.08; IR
3385, 3133, 2959, 1735 cm-1. Anal. Calcd for C11H18N2O2: C,
62.83; H, 8.63; N, 13.32. Found: C, 62.59; H, 8.51; N, 13.48.
methanol/ethyl acetate): yield 17 g, 59%; mp 114-115 °C; [R]25
D
) +8.4 (c 2.0, CH3OH); 1H NMR 1.37-1.39 (d, J ) 6.80 Hz, 3H),
3.59-3.69 (m, 2H), 4.14-4.18 (m, 1H), 5.84 (br, OH), 6.82 (s,
1H), 6.90 (s, 1H), 7.37 (s, 1H); 13C NMR δ 17.30, 55.77, 65.81,
117.29, 127.79, 135.93; IR 3116, 2980, 2938, 1578 cm-1; Anal.
Calcd for C6H10N2O: C, 57.12; H, 7.99; N, 22.20. Found: C,
56.99; H, 7.85; N, 22.02.
L-1-E t h yl-3-(1′-h yd r oxy-2′-p r op a n yl)im id a zoliu m Br o-
m id e (10a ). Under vigorously stirring, 76.3 g of bromoethane
was added dropwise to a solution of 25.2 g of 9a in 200 mL of
1,1,1-trichloroethane over 0.5 h.22 The mixture was stirred for
an additional 5 h under reflux and then evaporated to dryness.
The resultant product was further purified by column chroma-
tography (1:2, methanol/ethyl acetate): yield 43 g, 80%; mp 5-6
L-2-(1-Im id a zolyl)-4-m eth ylp en ta n ol (9c). This compound
was prepared by a procedure similar to that for the preparation
of 9a and was further purified by column chromatography (1:5
petroleum ether/ethyl acetate): yield 22 g, 57%; mp 53 °C; [R]25
D
) -10.8 (c 2.0%, CH3OH); 1H NMR δ 0.85-0.87 (d, J ) 6.40
Hz, 3H), 0.88-0.89 (d, J ) 6.80 Hz, 3H), 1.28-1.40 (m, 1H),
1.50-1.57 (m, 1H), 1.67-1.75 (m, 1H), 3.71-3.77 (m, 2H), 4.11-
4.16 (m, 1H), 4.33 (br, OH), 6.90 (m, 2H), 7.37 (s, 1H); 13C NMR
δ 21.73, 22.97, 24.46, 40.11, 59.03, 65.67, 117.24, 128.38, 136.43;
IR 3115, 2958, 2871, 1659 cm-1. Anal. Calcd for C9H16N2O: C,
64.25; H, 9.59; N, 16.66. Found: C, 64.45; H, 9.40; N, 16.39.
°C; [R]25 ) +3.7 (c 2.0%, CH3OH); 1H NMR 1.56-1.71 (m, 6H),
D
1.92 (br, OH), 3.43-3.48 (m, 2H), 3.73-3.78 (m, 1H), 4.36-4.38
(m, 2H), 4.87 (br, 1H), 7.35 (s, 1H), 7.45 (s, 1H), 9.86 (s, 1H); 13
C
NMR 15.21, 16.63, 45.37, 58.92, 64.54, 120.60, 121.05, 136.09.
IR 3444, 2078, 1634 cm-1; Anal. Calcd for C8H15BrN2O: C, 40.87;
H, 6.43; N, 11.91. Found: C, 40.62; H, 6.56; N, 11.79.
L-Eth yl 2-(1-Im id a zolyl)-3-m eth ylbu ta n oa te (8b). This
compound was prepared by a procedure similar to that for the
preparation of 8a and was further purified by column chroma-
tography (1:4 petroleum ether/ethyl acetate): yield 27 g, 68%
L-1-E t h yl-3-(1′-h yd r oxy-4′-m et h yl-2′-p en t a n yl)im id a zo-
liu m Br om id e (10c). This compound was prepared by a
procedure similar to that for the preparation of 10a and was
further purified by column chromatography (1:10 methanol/ethyl
(two steps overall); oil (bp 137-138 °C/7 mmHg); [R]25 ) +9.9
D
acetate): yield 50 g, 81%; mp 15-16 °C; [R]25 ) +9.2 (c 2.0%,
(c 2.0%, CH3OH); 1H NMR δ 0.79-0.80 (d, J ) 6.71 Hz, 3H),
1.00-1.02 (d, J ) 6.69 Hz, 3H), 1.26-1.30 (t, J ) 7.14 Hz, 3H),
2.39-2.44 (m, 1H), 4.17-4.25 (m, 2H), 4.31-4.33 (d, J ) 9.58
Hz, 1H), 7.06 (s, 1H), 7.11 (s, 1H), 7.59 (s, 1H); 13C NMR 13.91,
18.38, 19.12, 31.98, 61.59, 66.45, 118.38, 129.16, 137.02, 169.30;
D
1
CH3OH); HNMR δ 0.92-0.93 (d, J ) 6.40 Hz, 3H), 0.94-0.96
(d, J ) 6.40 Hz, 3H), 1.42-1.50 (m, 1H), 1.57-1.61 (t, J ) 7.00
Hz, 3H), 1.64-1.72 (m, 1H), 1.75-1.83 (m, 1H), 2.93 (br, OH),
3.74-3.77 (m, 1H), 3.90-3.93 (m, 1H), 4.33-4.39 (q, J ) 7.20
Hz, 2H), 4.70 (br, 1H), 7.40 (s, 1H), 7.42 (s, 1H), 9.67 (s, 1H);
13C NMR δ 15.10, 22.07, 22.67, 24.76, 39.32, 45.32, 62.00, 63.77,
120.94, 121.36, 136.36; IR 3385, 2959, 2873, 1636 cm-1. Anal.
Calcd for C11H21BrN2O: C, 47.66; H, 7.64; N, 10.11. Found: C,
47.70; H, 7.84; N, 10.00.
IR 3386, 3114, 2971, 2878, 1742 cm-1
. Anal. Calcd for
C10H16N2O2: C, 61.20; H, 8.22; N, 14.27. Found: C, 61.45; H,
8.31; N, 14.06.
L-2-(1-Im id a zolyl)-3-m eth ylbu ta n ol (9b). This compound
was prepared by a procedure similar to that for the preparation
of 9a and was further purified by column chromatogramphy (1:
10 methanol/ethyl acetate): yield 22 g, 60%; mp 95-97 °C; [R]25
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13CNMR,
and IR spectra of compounds 8a -c, 9a -c, and 10a -c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
D
) -20.5 (c 2.0, CH3OH); 1H NMR 0.73-0.74 (d, J ) 6.70 Hz,
3H), 1.02-1.03 (d, J ) 6.66 Hz, 3H), 2.08-2.13 (m, 1H), 3.66-
(26) Stuart, C. M.; Christine, S.; Tancarn, L.; Murray, M. A.; J ohn,
M. K. PCT Int. WO 97 19073.
J O020503I
J . Org. Chem, Vol. 68, No. 2, 2003 593