Synthesis and properties of chiral imidazolium ionic liquids with a (1R,2S,5R)-(-)-menthoxymethyl substituent

Article abstract of DOI:10.1039/b616215k

A series of 1-[(1R,2S,5R)-(-)-menthoxymethyl]-3-alkylimidazolium salts have been synthesized, producing both hydrophilic and hydrophobic chiral imidazolium ionic liquids. Their physicochemical properties, single-crystal X-ray structures, antimicrobial activities, and antielectrostatic effects were determined and these compounds have proven to represent not only potential new solvents in asymmetric synthesis, but also effective, disinfectants with antielectrostatic activity. Given the number and diversities of the possible conformations and interionic interactions, coupled with the chiral nature of the cations, it should come as no surprise that these salts exhibit ionic liquid behavior and are so difficult to crystallize. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Full text of DOI:10.1039/b616215k

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Synthesis and properties of chiral imidazolium ionic liquids with a
(1R,2S,5R)-(ꢀ)-menthoxymethyl substituentwz
Juliusz Pernak,*a Joanna Feder-Kubis,a Anna Cieniecka-Ros$onkiewicz,b
Cedric Fischmeister,c Scott T. Griffind and Robin D. Rogers*d
Received (in Cambridge, UK) 7th December 2006, Accepted 24th January 2007
First published as an Advance Article on the web 21st February 2007
DOI: 10.1039/b616215k
A series of 1-[(1R,2S,5R)-(ꢀ)-menthoxymethyl]-3-alkylimidazolium salts have been synthesized,
producing both hydrophilic and hydrophobic chiral imidazolium ionic liquids. Their
physicochemical properties, single-crystal X-ray structures, antimicrobial activities, and
antielectrostatic effects were determined and these compounds have proven to represent not only
potential new solvents in asymmetric synthesis, but also effective, disinfectants with
antielectrostatic activity. Given the number and diversities of the possible conformations and
interionic interactions, coupled with the chiral nature of the cations, it should come as no surprise
that these salts exhibit ionic liquid behavior and are so difficult to crystallize.
chiral solvents in the photoisomerization of dibenzobicy-
clo[2.2.2]octatriene diacid to induce enantiomeric excesses.23
Introduction
Ionic liquids (ILs) are now well known as salts with melting
The observed enantioselectivities, though modest in an abso-
points below 100 1C, and typically have broad liquid ranges,
lute sense, are among the highest achieved for unimolecular
photochemical reactions by use of a chiral environment.23
low vapor pressures, and may be both non-coordinating, but
highly polar. They are receiving considerable global attention
Successful procedures for the preparation of ILs containing
a chiral anion have been reported; including lactates3,11 and
because they offer a unique environment for chemistry, bio-
amino acids.24 In the literature, however, many more examples
catalysis, separation science, material synthesis, and electro-
chemistry.1 Among several classes of ILs, the newest class are
are noted of CILs in which chirality is related to the
chiral ionic liquids (CILs).2–18 They have attracted significant
cation. These are mainly imidazolium-,9,12,13,23 ammo-
nium-,4,13,14,21,23,25 pyridinium-26 and oxazolium-based4 ILs.
attention due to their potential application in chiral discrimi-
nation, asymmetric synthesis, and optical resolution of race-
mates.19,20 Very few methods for the synthesis of CILs have
imidazolium CILs directly obtained from the natural chiral
In this study, we present the synthesis and properties of
been described,9,13–18 and their real potential in asymmetric
pool of (1R,2S,5R)-(ꢀ)-menthol. Menthol, characterized by its
synthesis remains to be proven.
sharp, penetrating smell, belongs to the family of saturated,
Chirality in these salts can arise from either the anion or the
monocyclic, terpene alcohols. It has eight isomers, the struc-
cation. For example, a CIL in which the chirality was related
tures and names of which are listed in Scheme 1. Peppermint
to the anion, was used as the solvent in an asymmetric
or cornmint oil represents a rich source of menthol, obtained
Diels–Alder reaction.3 In the same reaction, a CIL with a
chiral cation was used as a Lewis acid.2 Good yields and
from various varieties of mints (Menthae L.), in which it can
comprise as much as 50% of the oil’s weight. It exhibits a
significant enantiomeric excesses were obtained when ammo-
soothing, anesthetic effect on mucous membranes and is
nium CILs were used as reaction media in the enantioselective
widely used in cosmetic and pharmaceutical industries.
version of the Baylis–Hillman reaction21 and aza-Baylis–Hill-
man reaction.22 The best enantioselectivity was obtained
(1R,2S,5R)-(ꢀ)-Menthol is a popular commercial and rela-
tively inexpensive isomer.
(44%) when the Baylis–Hillman reaction was performed for
seven days. Also, several CILs have been successfully used as
a
´
´
Poznan University of Technology, Poznan, Poland
b Institute of Industrial Organic Chemistry, Warsaw, Poland
c
´
CNRS-Universite de Rennes 1, Rennes, France
d Department of Chemistry and Center for Green Manufacturing, The
University of Alabama, Tuscaloosa, AL 35487, USA
w The HTML version of this article has been enhanced with colour
images.
z Electronic supplementary information (ESI) available: 1H and 13C
NMR data and elemental analysis for 1d–l, 2b–l, 8b–l and Table of
close contact interactions for 1a–1c (Table S1). See DOI: 10.1039/
b616215k
Scheme 1 Isomers of menthol.
ꢁc
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Scheme 3
essentially water, since the chlorides are strongly hygroscopic.
The chloride salts with methyl and ethyl substituents (1a, 1b
and 1m, respectively) manifested the highest melting tempera-
tures. Adding longer alkyl substituents resulted in a rapid
decrease in melting temperatures until oils were obtained.
Metathesis reactions of the chloride salts were carried out
using KBF4, NaClO4, KI, NaPF6, K(Ace) and NaCF3CO2.
Chiral imidazolium salts of [BF4]ꢀ, [ClO4]ꢀ, [I]ꢀ, [PF6]ꢀ,
[Ace]ꢀ and [CF3COO]ꢀ were obtained as crystalline materials
with sharply defined melting temperatures. Table 3 lists the
melting temperatures, specific rotation, and surfactant con-
tents as estimated by a direct two-phase titration technique,
using methanol as solvent. On the basis of the melting
temperatures, all of the salts listed in Table 3, except for 4
and 5, can be considered as CILs.
Scheme 2
Results and discussion
Syntheses
A series of chiral imidazolium salts of [Cl]ꢀ, [BF4]ꢀ, [ClO4]ꢀ,
[I]ꢀ, [PF6]ꢀ, [Ace]ꢀ (acesulfamate), [CF3COO]ꢀ, and [Tf2N]ꢀ
were prepared (Scheme 2) and their properties were deter-
mined. First, the 1-alkylimidazoles shown in Table 1 were
prepared by the reactions of imidazole with the appropriate
alkyl bromides in the presence of base (sodium in 1-propanol).
Quaternization was achieved using freshly distilled 1-alkylimi-
dazole and distilled chloromethyl (1R,2S,5R)-(ꢀ)-menthyl
ether. This ether is an excellent reagent, but it is readily
hydrolyzed to HCl, CH2O, and menthol. In view of this, these
reactions should be conducted under strictly anhydrous con-
ditions. Here, a suitable solvent proved to be anhydrous
hexane; from which the product precipitated. (In the cases of
1,2-dimethylimidazole and 1-benzylimidazole, dry DMF and
dry acetone were used, respectively.)
The new salts are water insoluble with the exception of the
[Ace]ꢀ and [CF3COO]ꢀ salts. Melting temperatures were
anion dependent as illustrated by the 1-[(1R,2S,5R)-(ꢀ)-
menthoxymethyl]-3-methylimidazolium salts: [Cl]ꢀ (1a) mp
= 137–138 1C, [I]ꢀ (4) mp = 127–129 1C, [PF6]ꢀ (5) mp =
125–126 1C, [BF4]ꢀ (2a) mp = 99–102 1C, [ClO4]ꢀ (3) mp =
98–99 1C, [Ace]ꢀ (6) mp = 62–63 1C, and [CF3COO]ꢀ (7)
mp = 20–21 1C. The length of the alkyl substituent showed an
even greater effect on melting points as shown for [Cl]ꢀ and
[BF4]ꢀ salts. The chloride salt with R1 = methyl (1a) melted at
137–138 1C, while the chloride salt, R1 = undecyl (1k) was an
oil at room temperature. Similarly, the [BF4]ꢀ salt with R1 =
methyl (2a) and R1 = undecyl (2k) had melting points of
99–102 and 28–30 1C, respectively.
The quaternization proceeded via
a specific type of
Menschutkin reaction involving an SN1 mechanism. The
initial rate-determining step was identified as involving forma-
tion of the cation, as show in Scheme 3. The cation thus
formed then reacted very rapidly with 1-alkylimidazole.
The synthesized chiral imidazolium chlorides (1, Table 2)
were obtained in very good yields and their specific rotations
were measured. The purities of these salts were determined by
a direct two-phase titration technique (EN ISO 2871-2: 1994)
and ranged from 97.5 to 99.9% (Table 2). The remainder was
All of the [Tf2N]ꢀ salts (8) are chiral imidazolium room
temperature ionic liquids (RTILs); the 12 representatives of
which are listed in Table 4. These hydrophobic salts were dried
in vacuum at 80 1C for 24 h and stored over P4O10. The water
contents, determined by Karl-Fischer measurements, were
found to be less than 500 ppm. After 41 days, these anhydrous
Table 1 Prepared 1-alkylimidazoles
R1
Yield (%)
Bp/1C
R1
Yield (%)
Bp/1C
CH3
91
85
83
90
74
79
76–77 @ 18 mmHg
97–98 @ 27 mmHg
89–90 @ 18 mmHg
114–116 @ 12 mmHg
119–120 @ 20 mmHg
135–136 @ 24 mmHg
C7H15
C8H17
C9H19
C10H21
C11H23
C12H25
81
83
78
85
79
83
153–154 @ 31 mmHg
151–152 @ 16 mmHg
174–175 @ 27 mmHg
172–173 @ 25 mmHg
167–168 @ 16 mmHg
199–200 @ 24 mmHg
C2H5
C3H7
C4H9
C5H11
C6H13
ꢁc
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Table 2 1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-2,3-dialkylimidazolium chlorides (1)
R1
R2
Yield (%)
Mp/1C
Surfactant content (%)
Specific rotationf >a]D
20
Chloride
1a
1b
1c
1d
1e
1f
1g
1h
1i
CH3
C2H5
C3H7
C4H9
C5H11
C6H13
C7H15
C8H17
C9H19
C10H21
C11H23
C12H25
CH3
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
96.5
89.5
74.0
96.0
99.0
97.5
99.5
99.5
97.0
97.0
99.0
99.0
99.0
99.5
137–138a
144–145a
73–74b
83–84c
55–58d
44–46d
Oil
Oil
Oil
Oil
Oil
97.9
97.8
98.2
97.4
98.5
99.3
97.5
97.5
99.6
99.5
99.9
99.9
98.1
97.9
ꢀ116.6 (c = 0.9)
ꢀ111.4 (c = 1.0)
ꢀ97.6 (c = 1.2)
ꢀ95.5 (c = 1.0)
ꢀ92.7 (c = 1.0)
ꢀ87.4 (c = 0.3)
ꢀ84.5 (c = 0.6)
ꢀ79.5 (c = 1.1)
ꢀ75.2 (c = 0.7)
ꢀ74.4 (c = 1.4)
ꢀ73.5 (c = 0.6)
ꢀ73.0 (c = 1.0)
ꢀ118.3 (c = 1.0)
ꢀ93.7 (c = 1.3)
d
1j
1k
1l
Oil
200–203e
67–69c
1m
1n
a
CH2Ph
b
c
From ethyl acetate–acetone–ethanol, needles. From ethyl acetate, large needles. From ethyl acetate–acetone, plates. From ethyl acetate,
e
plates. From ethyl acetate–chloroform–ethanol, plates. c in ethanol.
f
CILs were found to have absorbed water from the atmosphere
to a maximum level of 1.8% (Fig. 1).
ca. 230 1C. (The presence of oxygen decreased the decomposi-
tion temperature, as observed earlier for 1,3-dialkoxymethyl-
imidazolium salt-based ILs.28) In the first stage, the menthoxy
group is released, resulting in two estimated decomposition
temperatures (Td) (Table 4). The [Tf2N]ꢀ salts could not be
estimated by a direct two-phase titration technique, because
the [Tf2N]ꢀ anion in this ion pair is not interchangeable.
The [Tf2N]ꢀ CILs (8) are water insoluble, and more dense
than water. The densities range from 1.14 to 1.33 g mLꢀ1 and
decrease with increasing molar mass. Fig. 2 shows that there is
a linear relationship between the molar volume (calculated
from the equation Vm = M/d where d = density) and the
number of carbon atoms in the imidazolium alkyl group
substituent. These salts are insoluble in hexane and diethyl
ether, but are soluble in acetone, chloroform, DMF, THF,
ethyl acetate, toluene, DMSO, and low-molecular-weight
alcohols.
1
All synthesized salts were characterized by H NMR, 13C
NMR, and elemental analysis. The spectra were consistent
with the literature data.14,29 Protons of the H2C13 group,
which links the two rings, appear in the spectrum in the form
of two doublets. Manifestation of the diastereoisotopic pro-
tons was typical for all the studied salts, e.g., for 1a 5.69, 5.89
(d, J = 10.4 Hz, 2H, AB system).
The [Tf2N]ꢀ salts are all viscous liquids. Increases in molar
mass were accompanied by increases in viscosity, while in-
creasing the temperature results in a decrease in viscosity, as
shown in Fig. 3 for 8g. Additionally,27 as observed for other
ILs, the viscosity of these [Tf2N]ꢀ salts decrease upon addition
of water or other chemical impurities.
1
The H NMR spectra of the chlorides and the other salts
indicate different chemical shifts for the imidazolium ring
protons and methylene protons adjacent to the oxygen atoms
(Table 5). A strong anion effect was evident. Substitution of
the [Cl]ꢀ anion with [ClO4]ꢀ, [Ace]ꢀ, [I]ꢀ, [BF4]ꢀ, [PF6]ꢀ,
[Tf2N]ꢀ and [CF3COO]ꢀ resulted in changes in the imidazo-
lium ring electron density. A shift of 2 ppm between the [Cl]ꢀ
salt and the [PF6]ꢀ salt in the case of the HC12 group,
The specific rotation and thermal properties for the CILs 8
were established by DSC and TGA analyses, and are listed in
Table 4. For all these salts, the glass transition temperatures
(Tg), approached ꢀ50 1C, and all were thermally stable up to
Table 3 1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-alkylimidazolium salts (2–7)
R1
Anion
Yield [%]
Mp/1C
Surfactant content (%)
Specific rotationb [a]D
20
Salt
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
3
CH3
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[BF4]ꢀ
[ClO4]ꢀ
[I]ꢀ
99.5
99.5
99.5
99.5
98.5
98.5
99.0
98.5
99.0
98.5
99.5
98.5
99.5
99.5
99.5
98.0
97.0
99–102
66–68
52–54
27–28
60–61
59–60.5
76–78
77–79
70–71
42–43
28–30
40–42
98–99
127–129
125–126
62–63
20–21
97.5
97.7
98.2
97.3
99.9
97.5
99.9
99.9
96.5
97.5
99.9
98.3
97.6
97.5
97.7
98.0
97.9
ꢀ97.5 (c = 0.9)
ꢀ99.3 (c = 0.8)
ꢀ86.9 (c = 0.5)
ꢀ78.5 (c = 0.6)
ꢀ84.7 (c = 0.7)
ꢀ72.9 (c = 0.9)
ꢀ83.0 (c = 0.5)
ꢀ83.6 (c = 0.7)
ꢀ61.2 (c = 1.2)
ꢀ72.3 (c = 1.1)
ꢀ65.3 (c = 1.1)
ꢀ77.8 (c = 0.6)
ꢀ94.8 (c = 0.9)
ꢀ86.2 (c = 1.0)
ꢀ81.9 (c = 0.9)
ꢀ79.4 (c = 0.5)
ꢀ83.0 (c = 1.1)
C2H5
C3H7
C4H9
C5H11
C6H13
C7H15
C8H17
C9H19
C10H21
C11H23
C12H25
CH3
4
5
6
7
CH3
CH3
CH3
CH3
[PF]ꢀ
[Ace]ꢀ a
[CF3COO]ꢀ
a
b
Acesulfamate. c in ethanol.
ꢁc
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Table 4 1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-alkylimidazolium bis(trifluoromethanesulfonyl)imides (8)
Specific rotationa [a]D
Densityb/g mLꢀ1
Viscosityb/mm2 sꢀ1
Tonset/1C
Tdc/1C
Tgd/1C
20
Salt
R
Yield (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
CH3
87.9
91.2
87.8
91.6
94.3
89.1
89.9
87.9
93.4
91.4
92.1
98.9
c
ꢀ63.3 (c = 1.5)
ꢀ65.6 (c = 1.0)
ꢀ60.3 (c = 1.1)
ꢀ58.7 (c = 2.2)
ꢀ57.4 (c = 1.6)
ꢀ59.6 (c = 1.1)
ꢀ56.0 (c = 0.9)
ꢀ56.7 (c = 1.0)
ꢀ55.0 (c = 1.1)
ꢀ51.4 (c = 1.2)
ꢀ43.4 (c = 1.1)
ꢀ47.1 (c = 1.1)
1.33
1.30
1.29
1.27
1.26
1.24
1.22
1.21
1.19
1.17
1.15
1.14
302
338
379
421
444
447
469
505
542
567
572
580
230
225
230
230
230
225
230
225
230
230
230
230
250/470
250/470
250/475
250/470
250/475
250/470
250/475
250/470
250/470
250/475
250/470
250/475
ꢀ44
ꢀ46
ꢀ48
ꢀ51
ꢀ50
ꢀ50
ꢀ51
ꢀ50
ꢀ51
ꢀ51
ꢀ51
ꢀ51
C2H5
C3H7
C4H9
C5H11
C6H13
C7H15
C8H17
C9H19
C10H21
C11H23
C12H25
b
8j
8k
8l
a
d
c in ethanol. At 30 1C. Thermal degradation temperature. Glass transition temperature.
exemplifies the dramatic effect of the change in electron
density resulting from changing the anion. Similar observa-
tions concerning the ring protons were made by Fannin et al.
for 1-alkyl-3-methylimidazolium salts.30
menthoxymethyl]-3-propylimidazolium chloride hemihydrate
(1c ꢂ 0.5H2O). All three compounds have multiple ions in the
asymmetric unit (Fig. 4), due to the variable conformations of
the alkyl substituents and the menthol moiety, and the multi-
ple, variable, and weak interionic interactions. These multiple
configurations and interactions, and the chiral nature of the
compounds, makes obtaining suitable single crystals for ana-
lysis difficult (see Experimental section), however, this bodes
well for using these moieties to induce ‘ionic liquid’ behavior.
Here we briefly examine these factors by looking at the cation
conformations, the interionic interactions and the packing in
each case.
Comparing the differences between values of the chemical
shifts for the HC12 group, the anions can be ordered accord-
ing to their increasing shielding capacities as follows:
[Cl]ꢀ o [I]ꢀ o [CF3COO]ꢀ o [Ace]ꢀ o [ClO4]ꢀ o [BF4]ꢀ o
[Tf2N]ꢀ o [PF6]ꢀ
The most pronounced shielding abilities were noted for the
[PF6]ꢀ and [Tf2N]ꢀ anions. Additionally, the 13C NMR
spectra indicated notable differences in the chemical shifts
depending on the anion used. These shifts were most evident
for carbon C12; the differences between corresponding [Cl]ꢀ
and [Tf2N]ꢀ salts ranged from 1.5 to 3 ppm. The alkyl group
substitution in position 1 of the imidazole ring also affected the
shifts, e.g., 1.5 ppm for CH3 (salt 1a and 8a), but 3 ppm for
C2H5 (salt 1b and 8b) or C3H7 (salt 1c and 8c).
Cation conformations. Fig. 5 illustrates with cation overlays,
the distinct conformations of the menthol and alkyl groups
isolated. For 1a ꢂ H2O, the main differences between unique
cations lie in the torsion angle between the menthol and the
imidazolium moieties where N2–C13–O1–C6 = ꢀ81.2(2)1 for
one cation (O1) and 134.3(2)1 for the second cation (labeled
with primes) cation (O10).
Crystal structures
In 1b ꢂ 0.5H2O, the cations differ in two ways; the menthol
orientations (C12–N2–C13–O1 = 107.4(4)1 and ꢀ70.1(4)1 for
the unprimed and prime labeled cations (O1 and O10, respec-
tively) and the ethyl group orientations. In the cation contain-
ing the unprimed labeled cation (O1), the methyl end-group is
0.679(13) A on the opposite side of the plane of the
The crystal structures of three members of this series of
compounds were determined: 1-[(1R,2S,5R)-(ꢀ)-menthoxy-
methyl]-3-methylimidazolium chloride hydrate (1a ꢂ H2O), 1-
[(1R,2S,5R)-(ꢀ)-menthoxymethyl]-3-ethylimidazolium chlor-
ide hemihydrate (1b ꢂ 0.5H2O), and 1-[(1R,2S,5R)-(ꢀ)-
Fig. 2 Molar volume as a function of the number of carbon atoms in
the alkyl group in CILs 8.
Fig. 1 Maximum water content in hydrophobic CILs 8.
ꢁc
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while no p-overlap interactions were observed for 1b ꢂ 0.5H2O
(the only structure in the series with a cation that has the
menthol moiety and the alkyl substituent on opposite sides of
the imidazolium ring). In 1a ꢂ H2O (edge overlap), the ring
edge separations are 3.577(3) A for C9ꢂ ꢂ ꢂN10 and 3.425(3) A
for C11ꢂ ꢂ ꢂC12. (Note that this interaction does not cross the
polymeric water–chloride hydrogen bonded chain in the a
direction, but from adjacent cations along b.) Congestion of
the menthol moieties appears to prevent the cations from
further overlap.
For compound 1c ꢂ 0.5H2O, almost complete face-to-face
overlap of the imidazolium rings is observed. (Note that in this
structure the water–chloride hydrogen bond region is not
polymeric and the imidazolium rings are able to interact across
this region.) The average ring atomꢂ ꢂ ꢂring atom contact dis-
tance is 3.49(5) A and a very strict segregation of all ring
substituents to one side of the imidazolium ring is noted for
each unique cation.
Fig. 3 Viscosity of dry CIL 8g as a function of increasing tempera-
ture.
imidazolium ring from the menthol moiety, the only cation in
this series with this feature.
1c ꢂ 0.5H2O crystallizes with four cations, two solvent water
molecules, and four chloride anions in the asymmetric unit.
The cations can be divided into two pairs of similar orienta-
tions, one pair consisting of the cations containing oxygen
atoms O1 and O10 and the other containing O2 and O20. The
cations (O1, O10) have the n-propyl group extending out away
from the imidazolium ring with the N2–C10–C16–C17 torsion
angle nearly linear (177(1)1 av.), while in the other pair, (O2,
O20) the n-propyl group wraps over the imidazolium ring, on
the same side as the menthol moiety with the average torsion
angle being ꢀ48(1)1. It is noteworthy here (and important for
the p-stacking described below), that the menthol moiety
and alkyl substituent are on the same side of the imidazolium
ring.
In addition to the p-interactions, there are many close
contacts under van der Waals separations, including hydrogen
bonds between the cations, anions, and the water molecules
(Fig. 7). The strongest hydrogen bond interactions are be-
tween the chloride anions and the solvate water molecules (see
below), however, additional contacts are noted with the
imidazolium ring hydrogen atoms, the bridging methylene
hydrogen atoms, and even hydrogen atoms on the alkyl
substituents.
A few inter-cation interactions are also observed in each
structure. The closest such contacts include: in 1a ꢂ H2O be-
tween the menthol oxygen and hydrogen C11 on the imida-
zolium ring; in 1b ꢂ 0.5H2O between the menthol oxygen and
the C3 hydrogen atom in the menthol ring; and in 1c ꢂ 0.5H2O
between the menthol oxygen and the acidic C32 (C320) hydro-
gen atom on the imidazolium ring.
Interionic interactions. The weak interionic interactions ob-
served include both hydrogen bonding and p-stacking. Two
types of ring overlap interactions are observed (Fig. 6): face-
to-face stacking (1c ꢂ 0.5H2O) and edge overlap (1a ꢂ H2O),
The anions can be quite crowded when the cations pack
with the imidazolium end pointing towards the chloride anion,
1
Table 5 The chemical shiftsa in H NMR
Characteristic protons
Salt
Anion
HC12
HC9
HC11
H2C13
1a
2a
3
4
5
6
7
8a
[Cl]ꢀ
10.72 (t)
8.90 (t)
9.03 (t)
10.39 (t)
8.65 (t)
9.87 (t)
10.26 (t)
8.87 (t)
7.87 (t)
7.46 (t)
7.46 (m)
7.71 (t)
7.41 (t)
7.57 (t)
7.71 (t)
7.48 (t)
7.54 (t)
7.44 (t)
7.46 (m)
7.56 (t)
7.36 (t)
7.52 (t)
7.58 (t)
7.46 (t)
5.69, 5.89 (d, J = 10.4)
[BF4]ꢀ
[ClO4]ꢀ
[I]ꢀ
5.52, 5.60 (d, J = 10.7, J =10.4)
5.53, 5.63 (d. J = 10.7. J = 10.4)
5.69, 5.89 (d, J = 10.4)
5.49, 5.55 (d, J = 10.7, J = 10.4)
5.60, 5.74 (d, J = 10.4)
[PF6]ꢀ
[Ace]ꢀ b
[CF3COO]ꢀ
[N(SO2CF3)2]ꢀ
b
5.59, 5.75 (d, J = 10.4, J = 10.7)
5.52, 5.59 (d, J = 10.4)
a
Shift in ppm and J in Hz. Acesulfamate.
ꢁc
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Fig. 4 ORTEP diagrams of (a) 1-[(1R,2S,5R)-(ꢀ)-menthoxymethyl]-3-methylimidazolium chloride hydrate (1a ꢂ H2O) (top left), (b) 1-
[(1R,2S,5R)-(ꢀ)-menthoxymethyl]-3-ethylimidazolium chloride hemihydrate (1b ꢂ 0.5H2O) (top right), and (c) 1-[(1R,2S,5R)-(ꢀ)-menthoxy-
methyl]-3-propylimidazolium chloride hemihydrate (1c ꢂ 0.5H2O) (bottom). The thermal ellipsoids are depicted at 50% probability and hydrogen
atoms have been omitted for clarity. The high thermal motion indicative of conformational disorder is discussed in the Experimental section.
allowing room for three or four cations to interact with each
anion. These environments can also be less crowded when the
cations pack opposite and parallel to each other across the
chloride anion, allowing for only two cations to interact with
the anion.
inhibitory concentration (MIC) and minimum bactericidal or
fungicidal concentration (MBC) were established and are
compared in Table 6 to the corresponding values for the
widely applied benzalkonium chloride (BAC), in which the
alkyl group represents a mixture ranging from C8H17 to
C18H37.
Packing interactions. Packing diagrams for 1a–c are shown
in Fig. 8 and illustrate how the cations are segregated with the
menthol moieties in hydrophobic regions and the imidazolium
rings into more hydrophilic regions. Hydrogen bonds between
the chloride anions and the water solvate molecules can be
seen in the hydrophilic regions between the imidazolium rings,
especially in the fully hydrated 1a ꢂ H2O where the
water–chloride hydrogen bonds form a polymeric chain run-
ning parallel to the b axis between the imidazolium rings. In
the hemihydrate structures, the hydrogen bonds are limited to
discrete units of water molecules between two chloride anions
and do not form polymeric chains. Given the number and
diversities of the possible conformations and interionic inter-
actions, coupled with the chiral nature of the cations, it should
come as no surprise that these salts exhibit ionic liquid
behavior and are so difficult to crystallize.
The mean MIC and MBC values for all the studied
microbes are plotted in Fig. 9. The results suggest a strong
effect of the alkyl substituent chain length on biological
activity. For example, the chloride salts containing alkyl
substituents with more than five carbon atoms should be
regarded as active, but those with nonyl, decyl, undecyl or
dodecyl substituents should be regarded as superactive.
The MIC and MBC values are comparable, indicating not
only a strong biostatic effect, but also high biocidal activity.
Furthermore, the activities were higher than that shown by
BAC and these exceptional imidazolium chlorides, thus pos-
sess, a broad spectrum of activity against microbes.
The [I]ꢀ, [CF3COO]ꢀ, [Ace]ꢀ, [ClO4]ꢀ, [BF4]ꢀ, [Tf2N]ꢀ and
[PF6]ꢀ salts can also be expected to be effective against
bacteria and fungi, as confirmed by the results obtained with
1-alkoxymethyl-3-methylimidazolium [Cl]ꢀ, [BF4]ꢀ and
[PF6]ꢀ.31 However, the chiral pool of (1R,2S,5R)-(ꢀ)-menthol
does affect the antimicrobial activity, and this is also noted for
lactates, where imidazolium L-lactates are more active than
imidazolium DL-lactates.11
Antibacterial activities
The chiral imidazolium chlorides were tested for antimicrobial
activity against rods, cocci, and fungi. Values of minimum
ꢁc
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similar absence of effect was observed for the one studied
representative of the [ClO4]ꢀ, 3, and [PF6]ꢀ, 5, salts.
On the other hand, the [Tf2N]ꢀ salts, 8, even if strongly
hydrophobic, demonstrated a strong tendency to drain the
surface charge. Thus, it is not the hydrophobic character, but
the state of aggregation which plays a significant role. Until
now, hygroscopic liquids or greasy substances have been
thought to be excellent antielectrostatic agents. Given our
results however, attention should certainly be given to hydro-
phobic ionic liquids which are potentially effective antielectro-
static agents.
Conclusions
By applying Menschutkin reaction conditions, a number of
chiral imidazolium-based ILs were synthesized, in which the
chirality originates from the cation, which was derivatized
form the natural chiral pool of (1R,2S,5R)-(ꢀ)-menthol. All
the obtained salts are stable in air, water, and commonly used
organic solvents. These ILs also included RTILs containing
the [Tf2N]ꢀ anion.
The 1-[(1R,2S,5R)-(ꢀ)-menthoxymethyl]-3-alkylimidazo-
lium chlorides demonstrated an extremely high activity against
microbes, with a wide spectrum of activity. The studied CILs
also possess antielectrostatic properties, however, their effec-
tiveness was dependent upon their state of aggregation at
room temperature, which is related to the type of anion and
length of the alkyl substituent on the imidazole ring. Thus,
CILs not only represent new potential media for asymmetric
synthesis, but also disinfectants with antielectrostatic activity.
Fig. 5 Overlay of (a) the two cations in 1a ꢂ H2O (top left); (b) the two
cations in 1b ꢂ 0.5H2O (top right); and (c) the cations in 1c ꢂ 0.5H2O:
O1, O2 (middle left), O10, O20 (middle right), O1, O10 (bottom left),
and O2, O20 (bottom right).
Antielectrostatic effects
The antielectrostatic effects observed are a result of two
quantities: the surface resistance and the half-life decay time.
The surface resistance, Rs (in O), has been calculated from
eqn (1):
Experimental
General methods
1H NMR spectra were recorded on a Mercury Gemini 300
spectrometer operating at 300 MHz, with tetramethylsilane as
the internal standard. 13C NMR spectra were obtained with
the same instrument at 75 MHz. Elemental analyses were
Rs = Ul/is
(1)
where U is the applied voltage (U = 100 V), l is the length of
electrodes (l = 100 mm), i is the measured current intensity
(i = A), and s is the distance between the electrodes
(s = 10 mm). The half-life decay time, t1/2 (in s), was determined
from eqn (2):
performed at the A. Mickiewicz University, Poznan. Melting
´
points were determined using a model JA 9100 electrothermal
digital melting-point apparatus. Optical rotations were mea-
sured with a Perkin-Elmer 243 B polarimeter.
rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
Glass transitions were measured using a Perkin-Elmer
differential scanning calorimeter. The instrument temperature
scale was calibrated at the crystal–crystal transition of cyclo-
pentane (ꢀ151.16 1C) and the melting point of indium
(+156.6 1C). Samples were sealed in aluminum pans and
scanned at a rate of 20 K minꢀ1 in a helium atmosphere. A
Mettler Toledo DA 110 M scale was used for the mass/density
measurements. A micro Ostwald viscometer was used for
viscosity measurements. Simultaneous TG/DTA experiments
were performed using a MOM (Hungary) Derivatograph-PC.
t2þ þ t2ꢀ
t1=2
¼
ð2Þ
2
where t+ and t are the mean half-decay times of positive and
ꢀ
negative charges, respectively. The reported antielectrostatic
effects were determined following the criteria listed in Table 7
and presented in Table 8.
The 1-[(1R,2S,5R)-(ꢀ)-menthoxymethyl]-3-alkylimidazo-
lium chlorides 1a–l demonstrated an excellent antielectrostatic
effect. Their ability to drain the surface charge reflected their
strong hygroscopic properties. Introduction of an additional
methyl group to the imidazole ring, as well as, the presence of
an aromatic ring in the molecule, markedly inhibits the drain-
ing of surface charge (Table 8, chlorides 1m and 1n). However,
the [BF4]ꢀ salts 2, do not exhibit antielectrostatic properties. A
Syntheses
Chloromethyl (1R,2S,5R)-(ꢀ)-menthyl ether was prepared by
passing HCl through
a mixture of formaldehyde and
(1R,2S,5R)-(ꢀ)-menthol, following the published method.14
ꢁc
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Fig. 6 p-Interactions in (a) 1a ꢂ H2O (top) and (b) 1c ꢂ 0.5H2O (bottom).
Preparation of 1-alkylimidazole. Imidazole (13.60 g, 0.20
mol) was carefully added to a solution of sodium (5 g, 0.22
mol) in 1-propanol (200 mL), and mixed by stirring in a
round-bottomed flask, equipped with a magnetic stirring
bar, a reflux condenser, and an addition funnel. Following
the addition of imidazole, the mixture was heated at reflux to
form a clear solution. The solution was cooled to room
temperature and 150 mL of chloroform was added. The
organic phase was washed with distilled water, dried over
(Na2SO4), concentrated by rotoevaporation, and distilled to
give the corresponding 1-alkylimidazole.
10.7 Hz, J = 4.4 Hz, 1H, H6), 4.47 (q, J = 14.8 Hz, J = 7.4
Hz, 2H, H10), 5.68 and 5.95 (d, J = 10.4 Hz, 2H, AB system,
H13), 7.49 (t, J = 1.9 Hz, 1H, H11), 7.66 (t, J = 1.9 Hz, J =
1.6 Hz, 1H, H9), 11.06 (t, J = 1.1 Hz, 1H, H12); 13C NMR
(CDCl3): d 15.4 (C16), 15.5 (C14 or C15), 20.8 (C7), 22.0 (C14
or C15), 22.6 (C1), 25.3 (C8), 31.0 (C3), 33.9 (C4), 40.2 (C2),
45.3 (C10), 47.6 (C5), 76.6 (C6), 79.6 (C13), 121.0 (C11), 122.1
(C9), 137.6 (C12); elemental analysis: calc. (%) for
C16H29ClN2O (300.87): C 63.87, H 9.72, N 9.31; found: C
64.02, H 9.63, N 9.01.
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-methylimidazolium
1
General procedure for quaternization. Chloromethyl
(1R,2S,5R)-(ꢀ)-menthyl ether (0.02 mol) was added dropwise
into a round-bottomed flask which contained a vigorously
stirred mixture of 30 mL dry hexane and freshly distilled 0.02
mol of 1-alkylimidazole (in the case: 1,2-dimethylimidazole or
1-benzylimidazole, dry DMF or dry acetone was used, respec-
tively). The reaction mixture was stirred at room temperature
for 30 min. Then, the phases were separated and the crude
product was washed twice with dry hexane (2 ꢃ 30 mL). The
volatile materials were removed under reduced pressure at
60 1C overnight.
chloride (1a). H NMR (CDCl3, 25 1C): d 0.52 (d, J = 6.9
Hz, 3H, H14 or H15), 0.89 (m, 9H, Ha-4, H7, H14 or H15,
Ha-2 and Ha-1), 1.24 (m, 1H, H5), 1.42 (m, 1H, H3), 1.63
(m, 2H, Hb-1 and Hb-4), 1.95 (m, 1H, H8), 2.12 (m, 1H, Hb-
2), 3.37 (td, J = 10.4 Hz, J = 4.4 Hz, 1H, H6), 4.16 (s, 3H,
H10), 5.69, 5.89 (d, J = 10.4 Hz, 2H, AB system, H13), 7.54
(t, J = 1.9 Hz, J = 1.6 Hz, 1H, H11), 7.87 (t, J = 1.9 Hz, J
= 1.6 Hz, 1H, H9), 10.72 (t, J = 1.2 Hz, 1H, H12); 13C
NMR (CDCl3): d 15.1 (C14 or C15), 20.4 (C7), 21.6 (C14 or
C15), 22.3 (C1), 24.9 (C8), 30.6 (C3), 33.5 (C4), 36.2 (C10),
39.8 (C2), 47.2 (C5), 76.4 (C6), 79.1 (C13), 120.7 (C11),
124.0 (C9), 137.2 (C12); elemental analysis: calc. (%) for
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-ethylimidazolium
chloride (1b). 1H NMR (2D spectra) (CDCl3, 25 1C): d 0.49 (d,
J = 7.1 Hz, 3H, H14 or H15), 0.88 (m, 9H, Ha-4, H7, H14 or
H15, Ha-2 and Ha-1), 1.24 (m, 1H, H5), 1.43 (m, 1H, H3),
1.60 (m, 5H, Hb-1, Hb-4 and H16), 1.94 (sept d, J = 6.9 Hz, J
= 4.7, 1H, H8), 2.12 (d, J = 12.0 Hz, 1H, Hb-2), 3.40 (td, J =
C
15H27ClN2O (286.85): C 62.81, H 9.49, N 9.77; found: C
63.01, H 9.51, N 9.47.
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-propylimidazolium
1
chloride (1c). H NMR (CDCl3, 25 1C): d 0.50 (d, J = 6.9
Hz, 3H, H14 or H15), 0.88 (m, 9H, Ha-4, H7, H14 or H15,
ꢁc
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Fig. 7 Close contact environments for the cations in (a) 1a ꢂ H2O (top row); (b) 1b ꢂ 0.5H2O (second row); and (c) 1c ꢂ 0.5H2O: O1, O10 (third row),
O2, O20 (fourth row). Cationꢂ ꢂ ꢂanion and cationꢂ ꢂ ꢂwater interactions are shown in columns one and two, cationꢂ ꢂ ꢂcation interactions are shown in
column three. Contacts shown are those at least ꢀ0.100 A under the sum of the van der Waals radii.
Ha-2 and Ha-1), 1.23 (t, J = 3.6 Hz, 3H, H17), 1.28 (m, 1H,
H5), 1.43 (m, 1H, H3), 1.58 (m, 2H, Hb-1 and Hb-4), 1.99
(m, 3H, H8 and H16), 2.11 (m, 1H, Hb-2), 3.41 (td, J = 10.4
Hz, J = 4.4 Hz, 1H, H6), 4.36 (t, J = 7.4 Hz, 2H, H10),
5.71 and 5.96 (d, J = 10.4 Hz, 2H, AB system, H13), 7.52 (t,
J = 1.6 Hz, 1H, H11), 7.66 (t, J = 1.9 Hz, J = 1.6 Hz, 1H,
H9), 11.01 (t, J = 1.2 Hz, 1H, H12); 13C NMR (CDCl3): d
10.5 (C17), 15.5 (C14 or C15), 20.8 (C7), 21.9 (C14 or C15),
22.7 (C1), 23.5 (C16), 25.3 (C8), 31.0 (C3), 33.9 (C4), 40.3
(C2), 47.6 (C5), 51.5 (C10), 76.6 (C6), 79.8 (C13), 121.0
(C11), 122.4 (C9), 137.8 (C12); elemental analysis: calc. (%)
for C17H31ClN2O (314.90): C 64.84, H 9.92, N 8.90; found:
C 64.97, H 9.79, N 8.79.
Hz, 3H, H14 or H15), 0.89 (m, 9H, Ha-4, H7, H14 or H15,
Ha-2 and Ha-1), 1.22 (m, 1H, H5), 1.39 (m, 1H, H3), 1.63 (m,
2H, Hb-1 and Hb-4), 1.93 (m, 1H, H8), 2.08 (m, 1H, Hb-2),
2.83 (s, 3H, H27), 3.29 (td, J = 10.7 Hz, J = 4.4 Hz, 1H, H6),
4.03 (s, 3H, H10), 5.68 and 5.73 (d, J = 10.9 Hz, 2H, AB
system, H13), 7.79 (d, J = 1.9 Hz 1H, H11), 7.90 (d, J = 1.9
Hz, 1H, H9); 13C NMR (CDCl3): d 10.3 (C27), 15.3 (C14 or
C15), 20.6 (C7), 21.9 (C14 or C15), 22.5 (C1), 25.2 (C8), 31.0
(C3), 33.8 (C4), 35.5 (C10), 40.0 (C2), 47.5 (C5), 76.0 (C6),
79.0 (C13), 121.5 (C11), 122.7 (C9), 144.8 (C12); elemental
analysis: calc. (%) for C16H29ClN2O (300.87): C 63.87, H 9.72,
N 9.31; found: C 63.72, H 9.93, N 9.29.
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-benzylimidazolium
chloride (1n). 1H NMR (CDCl3, 25 1C): d 0.39 (d, J = 6.9 Hz,
3H, H14 or H15), 0.86 (m, 9H, Ha-4, H7, H14 or H15, Ha-2
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-2,3-dimethylimidazo-
lium chloride (1m). 1H NMR (CDCl3, 25 1C): d 0.50 (d, J = 6.9
ꢁc
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aqueous solution of inorganic salt was added. The reaction
mixture was stirred at room temperature producing a hetero-
geneous mixture. The crude product was separated and
washed with distilled water until chloride ions were no longer
detected using AgNO3. The obtained salt was dried at 80 1C
for 24 h in vacuum.
In the cases of water-soluble salts, the water was first
evaporated and the remnants were dissolved in dry acetone.
The inorganic salt was separated and the solvent was evapo-
rated to obtain the product.
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-methylimidazolium
tetrafluoroborate (2a). 1H NMR (CDCl3, 25 1C): d 0.50 (d, J =
6.7 Hz, 3H, H14 or H15), 0.97 (m, 9H, Ha-4, H7, H14 or H15,
Ha-2 and Ha-1), 1.29 (m, 1H, H5), 1.43 (m, 1H, H3), 1.61 (m,
2H, Hb-1 and Hb-4), 1.97 (m, 2H, H8 and Hb-2), 3.30 (td, J =
10.7 Hz, J = 4.4 Hz, 1H, H6), 3.97 (s, 3H, H10), 5.52, 5.60 (d,
J = 10.4 Hz, 10.7 Hz, 2H, AB system, H13), 7.44 (t, J = 1.9
Hz, J = 1.6 Hz, 1H, H11), 7.46 (t, J = 1.9 Hz, J = 1.6 Hz,
1H, H9), 8.90 (t, J = 1.1 Hz, 1H, H12); 13C NMR (CDCl3): d
15.3 (C14 or C15), 20.9 (C7), 22.0 (C14 or C15), 22.6 (C1), 25.2
(C8), 31.0 (C3), 33.9 (C4), 36.3 (C10), 39.9 (C2), 47.7 (C5),
76.6 (C6), 79.5 (C13), 121.3 (C11), 124.0 (C9), 136.3 (C12);
elemental analysis: calc. (%) for C15H27BF4N2O (338.20): C
53.27, H 8.05, N 8.27; found: C 53.39, H 8.29, N 8.40.
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-methylimidazolium
1
perchlorate (3). H NMR (CDCl3, 25 1C): d 0.51 (d, J = 7.14
Hz, 3H, H14 or H15), 0.98 (m, 9H, Ha-4, H7, H14 or H15,
Ha-2 and Ha-1), 1.25 (m, 1H, H5), 1.49 (m, 1H, H3), 1.63 (m,
2H, Hb-1 and Hb-4), 1.95 (m, 1H, H8), 2.03 (m, 1H, Hb-2),
3.32 (td, J = 10.4 Hz, J = 6.3 Hz, J = 4.1 Hz, 1H, H6), 4.01
(s, 3H, H10), 5.53, 5.63 (d, J = 10.4 Hz, J = 10.7 Hz 2H, AB
system, H13), 7.46 (m, 2H, H11 and H9), 9.03 (t, J = 1.0 Hz,
1H, H12); 13C NMR (CDCl3): d 15.4 (C14 or C15), 20.9 (C7),
22.1 (C14 or C15), 22.6 (C1), 25.3 (C8), 31.0 (C3), 33.9 (C4),
36.6 (C10), 40.0 (C2), 47.7 (C5), 76.6 (C6), 79.6 (C13), 121.4
(C11), 124.0 (C9), 136.5 (C12); elemental analysis: calc. (%)
for C15H27ClN2O5 (350.84): C 51.35, H 7.76, N 7.98; found: C
51.29, H 7.66, N 7.79.
Fig. 8 Packing diagrams for (a) 1a ꢂ H2O (top, viewed down a), (b)
1b ꢂ 0.5H2O (middle, viewed down a), and (c) 1c ꢂ 0.5H2O (bottom,
viewed down c), illustrating the orientation of the cations into hydro-
phobic menthol regions and hydrophilic imidazolium regions, and the
strong chlorideꢂ ꢂ ꢂwater hydrogen bonds in light blue (a polymeric
chain in 1a ꢂ H2O and discrete units in 1b ꢂ 0.5H2O and 1c ꢂ 0.5H2O).
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-methylimidazolium
iodide (4). 1H NMR (CDCl3, 25 1C): d 0.53 (d, J = 6.9 Hz, 3H,
H14 or H15), 0.90 (m, 9H, Ha-4, H7, H14 or H15, Ha-2 and
Ha-1), 1.26 (m, 1H, H5), 1.47 (m, 1H, H3), 1.63 (m, 2H, Hb-1
and Hb-4), 2.03 (m, 1H, H8), 2.16 (m, 1H, Hb-2), 3.41 (td, J =
10.7 Hz, J = 4.4 Hz, 1H, H6), 4.17 (s, 3H, H10), 5.69, 5.89 (d,
J = 10.4 Hz, 2H, AB system, H13), 7.56 (t, J = 1.9 Hz, 1H,
H11), 7.71 (t, J = 1.9 Hz, J = 1.7 Hz, 1H, H9), 10.39 (t, J =
1.0 Hz, 1H, H12); 13C NMR (CDCl3): d 15.6 (C14 or C15),
20.8 (C7), 22.0 (C14 or C15), 22.7 (C1), 25.3 (C8), 31.0 (C3),
33.9 (C4), 37.1 (C10), 40.2 (C2), 47.6 (C5), 76.6 (C6), 79.7
(C13), 121.3 (C11), 124.0 (C9), 137.0 (C12); elemental analysis:
calc. (%) for C15H27IN2O (378.30): C 47.63, H 7.19, N 7.41;
found: C 47.54, H 7.28, N 7.33.
and Ha-1), 1.21 (m, 1H, H5), 1.44 (m, 1H, H3), 1.60 (m, 2H,
Hb-1 and Hb-4), 1.88 (m, 1H, H8), 2.04 (m, 1H, Hb-2), 3.38
(td, J = 10.4 Hz, J = 4.1 Hz, 1H, H6), 5.63 (s, 3H, H10), 5.67
and 5.88 (d, J = 10.4 Hz, J = 10.7 Hz, 2H, AB system, H13),
7.37 (m, 3H, H11 and Ph), 7.50 (m, 4H, H9 and Ph), 11.11 (m,
1H, H12); 13C NMR (CDCl3): d 15.3 (C14 or C15), 20.7 (C7),
21.9 (C14 or C15), 22.6 (C1), 25.2 (C8), 30.9 (C3), 33.8 (C4),
40.2 (C2), 47.5 (C5), 58.3 (C10), 76.6 (C6), 79.9 (C13), 121.6
(C11), 122.9 (C9), 128.9 (Ph), 129.3 (Ph), 129.4 (Ph), 133.9
(Ph), 137.7 (C12); elemental analysis: calc. (%) for
C21H31ClN2O (362.99): C 69.48, H 8.62, N 7.72; found: C
69.63, H 8.59, N 7.61.
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-methylimidazolium
hexafluorophosphate (5). 1H NMR (CDCl3, 25 1C): d 0.50 (d, J
= 6.9 Hz, 3H, H14 or H15), 0.88 (m, 9H, Ha-4, H7, H14 or
H15, Ha-2 and Ha-1), 1.24 (m, 1H, H5), 1.43 (m, 1H, H3),
General procedure for ion exchange. Chiral imidazolium
chlorides were dissolved in water or methanol and a saturated
ꢁc
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Table 6 MIC and MBC values (mM) of 1-[(1R,2S,5R)-(ꢀ)-menthoxymethyl]-3-alkylimidazolium chlorides
Chloride
Strain
1a
1b
1c
1d
1e
1f
1g
1.3
84
22
84
1h
0.5
21
2.6
21
2.6
5.2
5.2
1i
1j
1k
1l
BACa
M. luteus
MIC
MBC
MIC
28
216 41664
873 832
53
25
51
397
795
51
12
189
94
381
49
381
189
1522
94
94
49
5.8
91
47
365
23
730
91
730
47
91
23
23
1460
1460
1460
1460
2.8
174
11
0.25 o0.25 o0.25 o0.25
1.4
11
2.8
23
5
1.3
5
1.3
1.3
2.5
2.4
0.5
2.4
2.4
2.4
0.5
2.3
4.7
4.7
2.3
2.3
1.2
9.4
0.5
2.3
2.3
2.3
145
145
9.4
9.4
73
73
2.3
2.3
19
1.1
0.2
1.1
2.3
4.5
1.1
1.1
S. aureua
MBC 41745 41664
MIC 216 832
MBC 41745 41664
MIC 41745 1664
174
S. epidermidis
E. faecium
5.6
45
45
5.4
1.4
5.6
5.6
23
0.6
1.4
2.8
2.8
175
175
88
795
795
22
22
84
5.4
43
1.3
2.7
337
675
337
337
337
675
22
MBC 41745 41664 41590
351
11
42
10
19
M. catarrhalis MIC
MBC
E. coli
436
873
436
436
416
416
103
103
197
397
99
2.6
5.2
1.3
1.3
161
161
81
161
161
161
5.2
5.2
21
1.3
1.3
0.5
0.5
2.4
2.4
2.4
2.4
o0.25
o0.25
0.5
45
2.8
MIC
MBC
99
49
11
701
701
701
701
701
1403
22
1.1
S. marcescens
P. vulgaris
P. aeruginosa
B. subtilis
C. albicans
R. rubra
MIC 41745 41664 41590 41522
MBC 41745 41664 41590 41522
MIC 41745 41664 41590 41522
MBC 41745 41664 41590 41522
MIC 41745 41664 41590 41522 41460
MBC 41745 41664 41590 41522 41460
78
75
75
9.7
19
39
75
70
78
40
40
40
78
141
9.1
18
70
70
o0.25
o0.25
2.3
88
175
175
2.8
2.8
11
88
23
88
MIC
MBC
873
873
1664
1664
397
795
94
189
91
91
730
1460
730
1.3
1.2
22
22
84
167
84
1.3
2.5
2.5
5
1.2
9.7
9.7
MIC 41745 41664 41590 41522
MBC 41745 41664 41590 41522
MIC 41745 41664
MBC 41745 41664
174
351
87
21
42
42
19
19
19
9.1
2.3
4.5
1590 41522
1590 41522 41460
19
19
701
675
20
a
Benzalkonium chloride.
1.62 (m, 2H, Hb-1 and Hb-4), 1.97 (m, 2H, H8 and Hb-2), 3.29
(td, J = 10.7 Hz, J = 4.4 Hz, 1H, H6), 3.94 (s, 3H, H10), 5.49,
5.55 (d, J = 10.4 Hz, J = 10.7 Hz, 2H, AB system, H13), 7.36
(t, J = 1.9 Hz, J = 1.6 Hz, 1H, H11), 7.41 (t, J = 1.9 Hz, J =
1.6 Hz, 1H, H9), 8.65 (t, J = 1.1 Hz, 1H, H12); 13C NMR
(CDCl3): d 15.3 (C14 or C15), 20.9 (C7), 22.0 (C14 or C15),
22.7 (C1), 25.3 (C8), 30.9 (C3), 34.0 (C4), 36.3 (C10), 39.9
(C2), 47.8 (C5), 76.6 (C6), 79.7 (C13), 121.3 (C11), 123.9 (C9),
136.0 (C12); elemental analysis: calc. (%) for C15H27F6N2OP
(396.36): C 45.46, H 6.87, N 7.07; found: C 45.56, H 6.91, N
7.21.
(m, 2H, Hb-1 and Hb-4), 1.94 (m, 1H, H8), 2.02 (m, 1H, Hb-2),
3.30 (td, J = 10.7 Hz, J = 4.4 Hz, 1H, H6), 4.04 (s, 3H, H10),
5.59 and 5.75 (d, J = 10.4 Hz, J = 10.7 Hz, 2H, AB system,
H13), 7.58 (t, J = 1.9 Hz, J = 1.6 Hz, 1H, H11), 7.71 (t, J =
1.9 Hz, J = 1.6 Hz, 1H, H9), 10.26 (t, J = 1.0 Hz, 1H, H12);
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-methylimidazolium
acesulfamate (6). 1H NMR (CDCl3, 25 1C): d 0.48 (d, J = 7.1
Hz, 3H, H14 or H15), 0.87 (m, 9H, Ha-4, H7, H14 or H15,
Ha-2 and Ha-1), 1.21 (m, 1H, H5), 1.39 (m, 1H, H3), 1.61 (m,
2H, Hb-1 and Hb-4), 1.99 (m, 5H, H8, Hb-2 and anion H28),
3.31 (td, J = 10.4 Hz, J = 4.4 Hz, 1H, H6), 4.05 (s, 3H, H10),
4.45 (s, 1H, anion H29), 5.60 and 5.74 (d, J = 10.4 Hz, 2H, AB
system, H13), 7.52 (t, J = 1.9 Hz, J = 1.6 Hz, 1H, H11), 7.57
(t, J = 1.9 Hz, J = 1.6 Hz, 1H, H9), 9.87 (t, J = 1.0 Hz, 1H,
H12); 13C NMR (CDCl3): d 15.2 (C14 or C15), 20.7 (C7), 21.8
(C14 or C15), 22.5 (C1), 25.0 (C8), 30.8 (C3), 33.7 (C4), 36.1
(C10), 39.8 (C2), 47.4 (C5), 76.4 (C6), 79.0 (C13), 121.0 (C11),
123.6 (C9), 137.0 (C12); anion: 19.6 (C28), 101.8 (C29), 160.4
(C30), 169.3 (C31); elemental analysis: calc. (%) for
C19H31N3O5S (413.63): C 55.17, H 7.57, N 10.16; found: C
55.07, H 7.64, N 10.40.
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-methylimidazolium
1
trifluoroacetate (7). H NMR (CDCl3, 25 1C): d 0.48 (d, J =
6.9 Hz, 3H, H14 or H15), 0.87 (m, 9H, Ha-4, H7, H14 or H15,
Fig. 9 Mean MIC values (top) and MBC values (bottom) for
Ha-2 and Ha-1), 1.23 (m, 1H, H5), 1.39 (m, 1H, H3), 1.63
microorganisms.
ꢁc
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Table 7 Criteria for the estimation of the antielectrostatic effect
based on the surface resistance Rs (O) and half-charge decay time
t1/2 (s)
cium ATCC 49474, Moraxella catarrhalis ATCC 25238, Es-
cherichia coli ATCC 25922, Serratia marcescens ATCC 8100,
Proteus vulgaris NCTC 4635, Pseudomonas aeruginosa NCTC
6749, Bacillus subtilis ATCC 6633, Candida albicans ATCC
10231, Rhodothorula rubra (Demml 1889, Lodder 1934). Stan-
dard strains were supplied by the National Collection of Type
Cultures (NCTC) and London and American Type Culture
Collection (ATCC). Rhodothorula rubra was obtained from
the Department of Pharmaceutical Bacteriology, University of
log Rs
t1/2/s
Antielectrostatic effect
o9
o0.5
Excellent
Very good
Good
Sufficient
Insufficient
No antielectrostatic properties
9–9.9
0.51–2
2.1–10
10.1–100
4100
10–10.9
11–11.9
12–12.9
413
4600
Medical Sciences, Poznan.
´
13C NMR (CDCl3): d 14.8 (C14 or C15), 20.4 (C7), 21.5 (C14
or C15), 22.2 (C1), 24.8 (C8), 30.6 (C3), 33.5 (C4), 35.7 (C10),
39.5 (C2), 47.2 (C5), 76.2 (C6), 78.9 (C13), 121.0 (C11), 123.8
(C9), 137.5 (C12); anion: 114.9, 118.8 (C28), 159.8, 160.3,
160.7, 161.1 (C29); elemental analysis: calc. (%) for
C17H27F3N2O3 (364.46): C 56.02, H 7.48, N 7.69; found: C
56.17, H 7.52, N 7.55.
Antimicrobial activity test procedure. Antimicrobial activity
was determined by the tube dilution method. A series of chiral
imidazolium chloride dilutions was prepared in Muller–
¨
Hinton broth medium (bacteria) or Sabouraud broth medium
(fungi). Bacteria strains were cultured in Muller-Hinton broth
¨
for 24 h and fungi in Sabouraud agar for 48 h. A suspension of
the microorganisms, at a concentration of 106 cfu mLꢀ1, were
prepared from each culture and each dilution of the broth
medium was inoculated with one of the above-mentioned
suspensions in a 1 : 1 ratio. Growth (or lack thereof) of the
microorganisms was determined visually after incubation for
24 h at 37 1C (bacteria) or 48 h at 28–30 1C (fungi). The lowest
concentration, at which there was no visible growth (turbid-
ity), was taken as the MIC. Then, from each tube, one loopful
was cultured on an agar medium with inactivates (0.3%
lecithin, 3% polysorbate 80, and 0.1% cysteine L) and in-
cubated for 48 h at 37 1C (bacteria) or for 5 d at 28–30 1C
(fungi). The lowest concentration of chiral imidazolium salt
supporting no colony formation was defined as the MBC.
1-[(1R,2S,5R)-(ꢀ)-Menthoxymethyl]-3-methylimidazolium
bis(trifluoromethanesulfonyl)imide (8a). 1H NMR (CDCl3,
25 1C): d 0.50 (d, J = 6.9 Hz, 3H, H14 or H15), 0.88
(m, 9H, Ha-4, H7, H14 or H15, Ha-2 and Ha-1), 1.25
(m, 1H, H5), 1.40 (m, 1H, H3), 1.63 (m, 2H, Hb-1 and Hb-
4), 2.04 (m, 2H, H8 and Hb-2), 3.28 (td, J = 10.7 Hz, J = 4.4
Hz, 1H, H6), 3.97 (s, 3H, H10), 5.52, 5.59 (d, J = 10.4 Hz, 2H,
AB system, H13), 7.46 (t, J = 1.9 Hz, J = 1.6 Hz, 1H, H11),
7.48 (t, J = 1.9 Hz, J = 1.6 Hz, 1H, H9), 8.87 (t, J = 1.0 Hz,
1H, H12); 13C NMR (CDCl3): d 15.0 (C14 or C15), 20.6 (C7),
21.7 (C14 or C15), 22.6 (C1), 25.2 (C8), 30.9 (C3), 33.8 (C4),
36.1 (C10), 39.8 (C2), 47.5 (C5), 76.6 (C6), 79.7 (C13), 121.6
(C11), 124.1 (C9), 135.7 (C12); anion: 113.3, 117.5, 121.8,
126.0; elemental analysis: calc. (%) for C17H27F6N3O5S2
(531.67): C 38.40, H 5.13, N 7.91; found: C 38.45, H 5.30, N 7.76.
Antielectrostatic properties
The antielectrostatic effect was measured on a Wigofil poly-
ethylene film with a density of 150 g mꢀ2 that did not contain
any lubricants or antioxidants. From this 0.25 mm film, 12.5 mm
diameter disks were cut. The disks were washed in acetone
and then dried by placing them in an air-conditioned room.
Test microorganisms. The microorganisms were: Micrococ-
cus luteus NCTC 7743, Staphylococcus aureus NCTC 4163,
Staphylococcus epidermidis ATCC 49134, Enterococcus fae-
Table 8 Surface resistance Rs (O), half-charge decay time t1/2 (s), and antielectrostatic effect for the chiral imidazolium salts
Salt
log Rs
t1/2
Effect
Salt
log Rs
t1/2
Effect
1a
1b
1c
1d
1e
1f
1g
1h
1i
8.3
8.0
7.7
8.3
8.0
8.6
7.3
7.7
7.8
7.5
7.5
7.6
0.25
0.25
0.25
0.45
0.25
0.45
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Excellent
Insufficient
Good
2h
2i
2j
2k
2l
3
4
5
7
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
413
413
413
413
413
413
10
413
7.8
9.9
4600
4600
4600
4600
4600
4600
0.35
4600
0.2
None
None
None
None
None
None
Good
None
Excellent
Very good
Very good
Very good
Very good
Very good
Very good
Very good
Very good
Excellent
Very good
Very good
Very good
o0.1
0.2
0.2
1j
1k
1l
o0.1
0.9
0.2
0.2
9.5
9.5
9.6
9.3
9.5
9
9
8.8
0.95
0.75
0.35
0.55
0.75
0.3
0.25
0.2
0.9
1m
1n
2a
2b
2c
2d
2e
2f
12
4100
8.7
4600
4600
4100
4100
4600
4600
4600
10.0
413
413
12.3
12.0
413
413
413
None
None
Insufficient
Insufficient
None
9.8
9.5
9.8
None
None
0.55
0.95
2g
ꢁc
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A disk was rubbed on the surface with a cotton-swab soaked
with a 0.5% chloroform solution of each studied salt. Then,
the disk was hung up so that the chloroform could evaporate
spontaneously.
C340 and C350 atoms and the refinement proceeded with full
weighted atoms. Hydrogen atoms (except for those on O10
and O11) were placed in calculated positions 0.95 A from the
bonded carbon atom and allowed to ride on that atom with U
fixed at 1.2 ꢃ Ueq of the bonded atom. The hydrogen atoms on
the solvent water molecules could not be located and are not
included in the final refinement. Additional crystals of
1c ꢂ 0.5H2O were screened with careful review of the unit cell
and merging R value for the equivalent data; the best data set
was used in the final refinement.
The disks, covered with chiral imidazolium salts, were
stored for 24 h in an air-conditioned room at 20 ꢄ 2 1C and
a relative humidity of 55 ꢄ 5%. Finally, the surface resistance
and half-life decay time were measured. The measuring appa-
ratus and the method have recently been described else-
where.32 The relative error in the determination of these two
quantities did not exceed 5%.
.
Crystal data for 1a H2O. C15H29ClN2O2, M = 304.85,
orthorhombic, space group P212121, a = 8.2722(11), b =
11.2447(16), c = 37.776(5) A, V = 3513.8(8) A3, T = 173 K,
Z = 8, m(Mo-Ka) = 0.221 mmꢀ1, 22 770 reflections measured,
8353 unique, R1 = 0.0486, wR2 = 0.0765 [I 4 2s(I)].
X-Ray crystallography
Data were collected on a Bruker CCD area detector-equipped
diffractometer with graphite monochromated Mo-Ka (l =
0.71073 A) radiation and the structures solved using the
SHELXTL software package.33 Absorption corrections were
made with SADABS.34 The structures were refined by full-
matrix least-squares on F2. Details unique to each structure
are discussed below.
.
Crystal data for 1b 0.5H2O. C16H30ClN2O1.5, M = 309.87,
monoclinic, space group P21, a = 13.0143(14), b = 8.0671(8),
c = 17.9287(18) A, b = 103.636(2)1, V = 1829.2(3) A3, T =
173 K, Z = 4, m(Mo-Ka) = 0.212 mmꢀ1, 11 927 reflections
measured, 7007 unique, R1 = 0.0565, wR2 = 0.1478
[I 4 2s(I)].
Data collection and structure refinement for crystals of
1a ꢂ H2O proceeded normally. The initial unit cell determina-
tion resulted in the orthorhombic space group P212121, and
the atoms were readily located from the initial structure
solution. The positions of all non-hydrogen atoms were aniso-
tropically refined and the hydrogen atoms were located from
the Fourier difference map and refined isotropically.
.
Crystal data for 1c 0.5H2O. C17H32ClN2O1.5, M = 323.90,
monoclinic, space group P21, a = 9.4408(10), b = 34.119(4), c
= 12.1754(13) A, b = 90.292(2)1, V = 3921.8(7) A3, T = 173
K, Z = 8, m(Mo-Ka) = 0.200 mmꢀ1, 25 348 reflections
measured, 17 434 unique, R1 = 0.0672, wR2 = 0.1432
[I 4 2s(I)].
Suitable crystals of 1b ꢂ 0.5H2O were selected by determina-
tion of unit cell parameters for several crystals and analyzing
the standard deviations and the goodness-of-fit parameters.
The initial structure solution in the monoclinic space group
P21 resulted in large thermal parameters for the ethyl group on
the imidazole ring (C10, C16, C100 and C160) and for the
solvent water oxygen (O10), indicating possible disorder or
high thermal motion. An adequate disorder model could not
be resolved and the refinement proceeded with full weighted
atoms. Hydrogen atoms (except for those on O10) were placed
in calculated positions 0.95 A from the bonded carbon atom
and allowed to ride on that atom with U fixed at 1.2 ꢃ Ueq of
the carbon atom. The hydrogen atoms on the solvent water
molecule could not be located and thus, were not included in
the final refinement. Additional crystals of 1b ꢂ 0.5H2O were
screened and the best data set was used in the final refinement.
Suitable crystals of 1c ꢂ 0.5H2O were also selected by deter-
mination of unit cell parameters and analyzing the standard
deviations and the goodness-of-fit parameters for several
crystals. The initial unit cell determination resulted in the
orthorhombic space group P21212, however, closer examina-
tion indicated the possibility of a monoclinic space group, P21.
The non-hydrogen atoms were readily located, but high
thermal parameters were noted for the terminal carbon atoms
on the n-propyl groups attached to the imidazole rings (C37A/
B and C37C/D) and for C340 and C350 in the isopropyl group
on one of the menthol groups. The disorder on the n-propyl
groups was resolved with two positions for each disordered
carbon atoms, each at 50% occupancy. These disordered
atoms were refined in alternate least-squares cycles. An ade-
quate disorder model could not be resolved for the isopropyl
CCDC reference numbers 613884–613886 (1a–1c).
For crystallographic data in CIF or other electronic format
see DOI: 10.1039/b616215k
Acknowledgements
This work was supported by the COST D29 working group
D29/0015/04 and at The University of Alabama by the U.S.
Environmental Protection Agency’s STAR program through
grant number RD-83143201. (Although the research described
in this article has been funded in part by EPA, it has not been
subjected to the Agency’s required peer and policy review and
therefore does not necessarily reflect the views of the Agency
and no official endorsement should be inferred.)
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This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
892 | New J. Chem., 2007, 31, 879–892