Synthesis and properties of novel chiral imidazolium-based ionic liquids derived from carvone

Article abstract of DOI:10.1039/c6ra00654j

A large series of novel chiral imidazolium ionic liquids were synthesized using the terpenoid carvone as the chiral substrate. Their specific rotations were characterized and their potential use in chiral recognition was demonstrated by studying interactions with racemic Mosher's acid salt.

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ARTICLE
Synthesis and properties of novel chiral imidazolium-based ionic
liquids derived from carvone
Francisco Santamarta,a Miguel Vilas, a Emilia Tojo*a and Yagamare Fall *a
Received 00th January 20xx,
Accepted 00th January 20xx
A large series of novel chiral imidazolium ionic liquids were synthesized using the terpenoid carvone as the chiral
substrate. Their specific rotations were characterized and their potential use in chiral recognition was demonstrated by
studying interactions with racemic Mosher’s acid salt.
DOI: 10.1039/x0xx00000x
www.rsc.org/
O
OH
OH
NaBH4
m-CPBA
O
-36 ºC, 20h
86%
CeCl3.7H2O
97%
R-3
R-2
(R)-1
N
60 ºC, 24h
99%
Introduction
NH
Over the past few years, chiral ionic liquids (CILs),
have received considerable attention as promising
materials for a variety of applications.1Although a
limited number of CILs have been designed and
synthesized, they have already shown successful results
as chiral solvents for optical resolution,2 as green
organic catalysts in asymmetric synthesis3 and as a
chiral stationary phase in chromatography.4
OH
OH
OH
RX
MY
X
OH
N
OH
N
OH
N
Y
R
N
N
R
N
R-4
R-5a-c
R-6a-i
Scheme 1
.
General synthetic procedure used to prepare the new CLIs
derived from (R)ꢀcarvone (R)-1
Most of the known chiral ionic liquids are derived from
chiral pools.5The latter provide limited scope for further
structural modifications. Carvone (1) is a terpenoid
found naturally in many essential oils.6
It’s commercially available in both enantiomeric forms,
and provides an easy and cost effective access to
optically pure functionalized compounds.
The series of enantiomers S-5 and S-6 were also
prepared by using a similar procedure starting from (S)ꢀ
carvone. To distinguish between them, those
compounds derived from (R)ꢀcarvone were named using
the prefix R and those derived from (S)ꢀcarvone were
named by using the prefix S.
First the (R)ꢀcarvone ketone group was regioselectively
reduced by treatment with NaBH4 in the presence of
Results and discussions
7
CeCl3 to afford the known allylic alcohol R-2.
8
Treatment of R-2 with mꢀCPBA in CH2Cl2 gave the
We anticipated that we could use carvone for the design
and synthesis of novel chiral ionic liquids with the
possibility of an easy structural refinement. Accordingly
target new CILs R-5 and R-6 derived from (R)ꢀcarvone
(R)-1 were prepared as outlined in Scheme 1.
epoxyꢀalcohol R-3.9 The next step consisted in the
introduction of an imidazole heterocycle that would
allow ionic liquids preparation by
a
direct
quaternization reaction. Using imidazole as
a
nucleophile,10 the epoxide R-3 was opened in a
regioselective manner to yield diol R-4, which
incorporates 4 chiral centers. The imidazolium halides
R-5 were then prepared by direct alkylation of R-4 with
the corresponding alkyl halides. However, other new
CILs, the bridged oxabicycles R-11 (Scheme 2), were
a.Departamento de Química Orgánica,Facultad de Química and Instituto de
Investigación Biomedica (IBI), University of Vigo, Campus Marcosende, 36310
Vigo, Spain.
E-mail: etojo@uvigo.es; yagamare@uvigo.es
Electronic Supplementary Information (ESI) available: Experimental details and
Spectroscopic data of all new compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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also obtained when long reaction times were employed Table 1.Preparation and characterization of both series
or when an alkyl bromide was used as alkylating agent.
of CILs
Rto
(%)
66
61
76
[α]20
Compounds RX
t (d)
CIL
D
Rꢀ4
Rꢀ4
Rꢀ4
7
8
9
5
3
7
Rꢀ5a
Rꢀ5b
Rꢀ5c
Rꢀ
11a
Rꢀ
11b
Rꢀ
11c
ꢀ43
ꢀ27
ꢀ28
Rꢀ4
Rꢀ4
Rꢀ4
8
10
9
9
3
9
89
91
79
ꢀ51
ꢀ52
ꢀ53
Sꢀ4
Sꢀ4
Sꢀ4
Sꢀ4
7
8
9
8
6
2
7
8
Sꢀ5a
Sꢀ5b
Sꢀ5c
Sꢀ11a
Sꢀ
90
82
75
40
+42
+28
+27
+50
Scheme 2 Preparation of halide salts by direct alkylation
.
When R-4 was heated with the alkyl chlorides 7-9 for 3ꢀ
7 days, the corresponding dihydroxylated salts R-5a-c
were obtained (Table 1). However, the use of longer
reaction times (8ꢀ9 days) or the bromide 10, afforded
the bridged oxabicycles R-11a-c. These unexpected
results can be explained by an electrophilic addition of
the neighboring hydroxyl group to the isopropenyl
double bond, through a cis 1,3ꢀdiaxial attack.
Sꢀ4
Sꢀ4
10
9
3
9
74
77
+50
+52
11b
Sꢀ11c
Finally, a series of different anions were introduced by
metathesis reactions carried out by treatment of the
dihydroxylated halide salts R-5a-c and the bridged
oxabicycles R-11b-c with different inorganic salts
(Schemes 4 and 5). A similar procedure was applied
starting from corresponding enantiomers S-5a-c and S-
11b-c. The inorganic salts used in each case and the
optical rotations of the CILs obtained are indicated in
Table 2. The structures of all the novel CILs were
characterized by 1H NMR, 13C NMR, 19F NMR, IR and
high resolution MS.
When the above procedure was developed starting
from (S)-carvone (S)-1 instead of (R)-carvone (R)-1, the
corresponding enantiomers S-5a-c and S-11a-c were
obtained, as indicated in Scheme 3.
OH
OH
OH
OH
Y-
MY
Cl-
Scheme 3 Preparation of halide salts from (S)ꢀcarvone (S)-1
.
N
NR
N
NR
Table 1 shows the results of the quaternization reactions
and the characterization of both series of enantiomeric
CILs.
R-6a
, Y = BF4, R = C4H9
R-6b, Y = NTf2, R = C4H9
R-6c
R-5a
, R = C4H9
R-5b, R = C6H13
R-5c
, Y = MeSO4, R = C4H9
R-6d, Y = TFA, R = C6H13
R-6e
, R = C8H15
, Y = NTf2, R = C6H13
R-6f, Y = MeSO4, R = C6H13
R-6g
MY: NaBF4
NaTFA
, Y = TFA, R = C8H15
R-6h, Y = NTf2, R = C8H15
R-6i
LiNTf2
, Y = MeSO4, R = C8H15
NaMeSO4
2 | J. Name., 2012, 00, 1-3
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Scheme 4. Metathesis reactions from dihydroxylated
carvone. All of them were found to be liquid at room
temperature except chlorides 5a.
chlorides R-5a-c
The enantiomeric recognition ability of all the new
synthesized CILs was tested by investigating their
diastereomeric interaction with the racemic substrate
Mosher's acid potassium salt, by 1H and 19F NMR. First
chlorides R-5a and S-5a were dissolved in (CD3)2CO
and stirred with racemic Mosher’s carboxylate using
different concentrations of CIL. Due to the chiral
environment produced by the CILs, the NMR signals
corresponding to the MeO and CF3 groups of the
racemic substrate were split (Table 3).
Table 3. Splitting of MeO and CF3 NMR signals of
Mosher’s salt in the presence of the CILs R-5a and S-
5a.
[Rꢀ5a]
(equiv)
0
1.5
∆δ
∆δ
(1H)[Hz]
2
[H2O] (%)
(19F)[Hz]
Scheme 5. Metathesis reactions from oxabicycles R-
0
0
14
15
11b-c
3.9
2.25
2.25
[Sꢀ5a]
(equiv)
0
1.25
2.25
2.25
0
0.04
18
0
3.1
0
∆δ
∆δ (1H)
[Hz]
4.2
Table 2. Metathesis reactions and optical rotations of
the obtained CILs
[H2O] (%)
(19F)[Hz]
0
0
0
30
36
34
0
R
[α]20
ꢀ35
ꢀ22
ꢀ32
ꢀ26
ꢀ15
ꢀ26
ꢀ34
ꢀ14
ꢀ20
ꢀ53
ꢀ42
ꢀ56
ꢀ53
ꢀ42
ꢀ20
ꢀ29
S
Starting
material
Inorganic salt CIL
[α]20
4.6
4.4
0
D
D
5a
5a
5a
5b
5b
5b
5c
5c
5c
11b
11b
11b
11b
11c
11c
11c
NaBF4
LiNTf2
6a
6b
+33
+21
+31
+27
+14
+25
+33
+15
+21
+52
+41
+54
+55
+43
+19
+30
0.04
NaMSO4
NaTFA
LiNTf2
6c
6d
6e
NaMSO4
NaTFA
LiNTf2
6f
6g
6h
NaMSO4
NaBF4
NaTFA
LiNTf2
NaMSO4
NaTFA
LiNTf2
6i
12a
12b
12c
12d
12e
12f
12g
The highest splitting was observed for the CF3 signal of
S-5a that showed a ∆δ = 36 when a concentration of
1.25 equiv of CIL was used (Figure 1).
NaMSO4
Altogether, 44 new enantiomerically pure salts based on
imidazolium cation derived from carvone incorporating
[Cl], [Br], [BF4], [NTf2], [TFA] and [MSO4] anions
were prepared, 22 from (R)ꢀcarvone and 22 from (S)ꢀ
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Figure 1.19F NMR signals of Mosher’s salts CF3 group
in the presence of 1.25 equiv of CIL S-5a
Figure 3.19F NMR spectrum of an (
R)ꢀenriched sample
of Mosher’s acid potassium salt in the presence of CIL
S-5a
The high chiral discrimination ability of CIL S-5a
prompted us to use it in the determination of the ee
value of enantiomerically enriched mixtures of
As we can see in Figures 1 and 2, the integration of the
CF3 signal of each enantiomer of Mosher’s carboxylate
can provide the exact amount of enantiomers, hence
could be used for ee determination.
Mosher’s carboxylate with approximately
2:1 (Figures 2 and 3).
R/S = 1:2, and
The bridged oxabicycle S-11a also proved to induce
high chiral discrimination (Figure 4).
Figure 4.19F NMR signals of Mosher’s salts CF3 group
in the presence of 1.25 equiv of CIL S-11a
Figure 2.19F NMR spectrum of an (
S)ꢀenriched sample
of Mosher’s acid potassium salt in the presence of CIL
S-5a
Conclusion
In summary, 44 new enantiomerically pure salts based on
imidazolium cation derived from carvone incorporating [Cl],
[Br], [BF4], [NTf2], [TFA] and [MSO4] anions were prepared, 22
4 | J. Name., 2012, 00, 1-3
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Heckel, A. Winkel, R. Wilhelm, Tetrahedron: Asymmetry.
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from (R)-carvone and 22 from (S)-carvone. All of them were
found to be liquid at room temperature except chlorides.
Their enantiomeric recognition ability was tested by
investigating their diastereomeric interaction with the racemic
substrate Mosher's acid potassium salt, by 1H and 19F NMR.
The high chemical shift dispersion induced by some of CILs
shows their potential applications in optical resolution of
racemates and in determining the enantiomeric excess of
enantiomerically enriched carboxylates by NMR spectroscopy.
We are currently studying the application of these CILs as
3
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Conclusions
In summary, 44 new enantiomerically pure salts based on
imidazolium cation derived from carvone incorporating [Cl],
[Br], [BF4], [NTf2], [TFA] and [MSO4] anions were prepared, 22
from (R)-carvone and 22 from (S)-carvone. All of them were
found to be liquid at room temperature except chlorides.
Their enantiomeric recognition ability was tested by
investigating their diastereomeric interaction with the racemic
substrate Mosher's acid potassium salt, by 1H and 19F NMR.
The high chemical shift dispersion induced by some of CILs
shows their potential applications in optical resolution of
racemates and in determining the enantiomeric excess of
enantiomerically enriched carboxylates by NMR spectroscopy.
We are currently studying the application of these CILs as
reaction media and as catalysts in asymmetric synthesis
6
7
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Acknowledgements
We thank the Xunta de Galicia (CN 2012/184, EM2013/031,
REGALIs Network R2014/015) and the Ministerio de Economía
y Competitividad of Spain (DPI2012-38841-C02-02) for their
financial support.The work of the NMR, SC-XRD and MS
divisions of the research support services of the University of
Vigo (CACTI) is also gratefully acknowledged.
Received: ((will be filled in by the editorial staff))
Revised: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
Notes and references
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