Synthesis and antimicrobial activity of imidazolium and triazolium chiral ionic liquids

Article abstract of DOI:10.1002/ejoc.201201245

A simple and efficient procedure for the synthesis of new optically active imidazolium and triazolium ionic liquids in a three step reaction sequence is described. In the first step, the ring opening of 1,2-butylene oxide by imidazole or 1,2,4-triazole re

Full text of DOI:10.1002/ejoc.201201245

FULL PAPER
DOI: 10.1002/ejoc.201201245
Synthesis and Antimicrobial Activity of Imidazolium and Triazolium Chiral
Ionic Liquids
Paweł Borowiecki,*[a] Małgorzata Milner-Krawczyk,[a] Dominika Brzezin´ska,[a]
Monika Wielechowska,[a] and Jan Plenkiewicz[a]
Keywords: Ionic liquids / Chirality / Enzyme catalysis / Kinetic resolution / Antibiotics / Antifungal agents
A simple and efficient procedure for the synthesis of new op-
tically active imidazolium and triazolium ionic liquids in a
three step reaction sequence is described. In the first step,
the ring opening of 1,2-butylene oxide by imidazole or 1,2,4-
triazole resulted in the formation of N-2-hydroxybutylimid-
were resolved with good enantioselectivity by a lipase-cata-
lyzed transesterification with enol esters (vinyl acetate and 1-
acetoxy-2-methylcyclohexene). In the final step, the optically
active intermediates were alkylated with several haloalkanes
to yield optically active ionic liquids. The inhibitory activity
azole and N-2-hydroxybutyl-1,2,4-triazole, respectively. In of the synthesized ionic liquids was tested towards gram-
the second step, racemic mixtures of the secondary alcohols
negative and gram-positive bacteria and fungi.
volatile organic solvents raises questions about the toxicity
of newly designed compounds. Therefore, it is crucial to
select an IL that combines low toxicity with good chemical
properties for use in industrial processes.[9] Moreover, recent
studies have demonstrated the potential of certain ionic li-
quids to exhibit excellent antimicrobial activity, which raises
the possibility that ionic liquids could find application as
biocidal agents in the control of the growth of microorga-
nisms.[10]
Nowadays, most CILs are prepared from naturally exi-
sting building blocks such as amino acids,[11] alkaloids,[12]
sugars,[13] hydroxy acids,[14] and other precursors from the
so-called chiral pool. Such an approach has many advan-
tages because these compounds are usually available in a
great amount and at low cost. On the other hand, it has
disadvantages such as a limited number of available struc-
tures. For this reason, chiral imidazolium and especially tri-
azolium ionic liquids containing one asymmetric carbon
atom on the side of the cation with free hydroxy function
were synthesized by an enzyme-catalyzed kinetic resolution
by two teams of researchers in 2011.[15] The chiral ILs may
be exploited in asymmetric synthesis as solvent and catalyst
in one to accelerate catalytic reactions. Also, the unknown
biological activity of these compounds is compelling, be-
cause the optically active secondary imidazolium alcohol
(S)-(+)-5a can serve as a key intermediate in the synthesis
of inhibitors of Ras farnesyl protein transferase (FPT).[16]
In turn, its acetyl ester (R)-(+)-6a is a QC-36 molecule that
exhibits anti-Plasmodium activity and is extremely impor-
tant in malaria treatment.[17]
Introduction
Ionic liquids (ILs) are salts consisting of an organic cat-
ion and an organic or inorganic anion with melting points
near ambient temperature (below 100 °C).[1] The existing
range of cation–anion combinations gives many possibil-
ities for modification of the structure of the IL, which re-
sults in their diverse chemical and physical properties. Ionic
liquids are often called “designer compounds”, as their
physical properties such as melting point, viscosity, density,
and hydrophobicity can be modified by altering the nature
of their cations and anions. ILs have attracted significant
consideration as environmentally friendly media for electro-
chemistry,[2] chemical engineering, materials science, and es-
pecially for organic synthesis.[3] The last one is evolutional
because the properties of the IL can be tuned according to
the desired reactions. Thus, comprehensive studies of com-
monly named task-specific ILs with controllable and func-
tionalized physical and chemical properties have recently
been carried out. Chiral ionic liquids (CILs) are particularly
interesting owing to their attractive applications for asym-
metric synthesis,[4] stereoselective polymerization,[5] chiral
gas chromatography,[6] NMR shift reagents,[7] and chiral li-
quid crystals.[8] The use of ILs in so called “green chemis-
try”, for example, as media for chemical engineering, or-
ganic synthesis, or a replacement for many hazardous and
[a] Warsaw University of Technology, Faculty of Chemistry,
Noakowskiego St. 3, 00-664 Warsaw, Poland
Fax: +48-22-628-27-41
E-mail: pawel_borowiecki@onet.eu
The ionic liquid field is dominated by imidazolium salts.
There are very few triazolium derivatives that can be char-
acterized as ionic liquids. Furthermore, until recently there
was a lack of chiral triazolium quaternary salts of the type
pborowiecki@ch.pw.edu.pl
Homepage: http://www.ch.pw.edu.pl/
http://ztibsl.ch.pw.edu.pl/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201245.
712
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Synthesis and Antimicrobial Activity of Chiral Ionic Liquids
prepared by us with melting points Ͻ 100 °C. Moreover, the
toxicity of the newly designed compounds has been verified
against a panel of microorganisms including gram-negative
and gram-positive bacteria and fungi.
acetate quantity, or even cooling). A detailed examination
of the reaction revealed that vinyl, isopropenyl, ethyl, and
butyl acetates are too reactive with the investigated alcohol
and react spontaneously even at low temperature without
any catalyst. On the other hand, when 4-nitrophenyl but-
yrate was used as the acylating agent, neither spontaneous
nor lipase-catalyzed reaction was observed. After these ex-
periments, we decided to check if some other bulky acetate
could terminate this undesirable hyperreactivity of the sim-
ple acetates. 1-Acetoxy-2-methylcyclohexene (9) was cho-
sen, as it is highly sterically hindered and can be easily pre-
pared from racemic 2-methylcyclohexanone by reaction
with acetic anhydride and a catalytic amount of perchloric
acid.[19] Finally, it turned out that its low reactivity prevents
a spontaneous transesterification and simultaneously works
as intended as an acyl donor in the lipase-catalyzed reac-
tion. The next problem to be solved was the solvent selec-
tion. From several examined solvents that are commonly
used in enzymatic reactions, we chose tert-amyl alcohol (2-
methylbutan-2-ol), in which the resolution of (Ϯ)-3a was
most effective (Table 2). After screening a few commercial
lipases (Table 2, Entries 1–4), we noticed that room-tem-
perature reactions with immobilized lipases (Novozym 435,
Amano PS-C) were much faster than those with native en-
zymes (Amano AK, Amano PS). Nevertheless, it appeared
that the reactions were significantly better catalyzed by the
native enzymes, which led to a substantial increase in
enantioselectivity (Table 2, Entries 2 and 3). The next two
experiments (Table 2, Entries 5 and 6) were performed with
Amano PS-IM lipase under modified conditions. We de-
creased the quantity of lipase and extend the reaction time
to 52% substrate conversion (Table 2, Entry 6). As a result,
the unreacted alcohol (+)-5a was obtained in high enantio-
meric excess (ee = 98%). To achieve the opposite enantio-
meric form of 1-(1H-imidazol-1-yl)butan-2-ol [(+)-6a] with
high optical purity, the reaction was stopped at close to
45% conversion (ee = 99%, Table 2, Entry 7).
Results and Discussion
Synthesis and Enzymatic Resolution of the N-2-
(Hydroxybutyl)azoles
We report useful and straightforward syntheses of several
optically active, liquid at room temperature quaternary
imidazolium and triazolium salts. This new group of chiral
ionic liquids has been prepared in a three step reaction se-
quence as presented in Scheme 1.
The first step of the process is based on solvent-free re-
gioselective ring opening[18] of 1,2-butylene oxide (1) with
imidazole (2a) or 1,2,4-triazole (2b). The neat reactions gave
(Ϯ)-trans-1-(1H-imidazol-1-yl)butan-2-ol [(Ϯ)-3a] and (Ϯ)-
trans-1-(1H-1,2,4-triazol-1-yl)butan-2-ol [(Ϯ)-3b] in yields
ranging from 77 to 99% depending on the conditions ap-
plied (Table 1).
Table 1. Ring opening of 1,2-butylene oxide (1) with imidazole (2a)
or 1,2,4-triazole (2b) under solvent-free conditions.
Entry Product Equiv. of epoxide Time [h] T [°C] Yield [%][a]
1
2
3
(Ϯ)-3a
(Ϯ)-3a
(Ϯ)-3a
1
1
1
12
24
72
60
45
60
82
77
99
4
(Ϯ)-3b
1.2
24
70
96
[a] Isolated yield.
The second step is the lipase-mediated kinetic resolution
of the racemic alcohols (Ϯ)-3a and (Ϯ)-3b. Preliminary
studies of this reaction were performed with (Ϯ)-3a. The
main difficulty was the vigorous course of the reaction,
which does not change even after modification of the condi-
tions (significant dilution, reduction of enzyme and vinyl
Scheme 1. Synthesis of optically active ILs. Reagents and conditions: (i) epoxide (1 equiv.), 60 °C, 72 h; (j) epoxide (1.2 equiv.), 70 °C,
24 h; (ii) Ac2O (1.05 equiv.), DMAP (0.33 equiv.), pyridine (14 equiv.), neat, room temp., 72 h; (jj) vinyl acetate (5 equiv.), enzyme, 2-
methyl-2-butanol, room temp.; (iii) 1-acetoxy-2-methylcyclohexene (2.5 equiv.), enzyme, 2-methyl-2-butanol, room temp., 250 rpm; (jjj)
vinyl acetate (5 equiv.) or 1-acetoxy-2-methylcyclohexene (2.5 equiv.), enzyme, 2-methyl-2-butanol, room temp., 250 rpm; (iv) and (jv) RX
(3 equiv.), Δ, dry CH3CN.
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Table 2. Lipase-catalyzed resolution of (Ϯ)-3a.
ranged from 89 to 100% for (S)-(+)-1-(1H-1,2,4-triazol-1-
yl)butan-2-ol [(+)-5b] and from 92 to 98% for (R)-(+)-1-
(1H-1,2,4-triazol-1-yl)butan-2-yl acetate [(+)-6b].
Entry
Enzyme
t
Conv.[e] Product ee[f] E[g] Yield[h]
[h]
[%]
[%]
[%]
The racemic acetates (Ϯ)-4a and (Ϯ)-4b were required
for the determination of the purity of the separated enantio-
merically enriched acetates. The acetate (Ϯ)-4a was pre-
pared by a classical procedure with acetic anhydride, pyr-
idine, and 2-dimethylaminopyridine (DMAP), but (Ϯ)-4b
was prepared in a lipase-catalyzed reaction because a con-
ventional esterification of the alcohol (Ϯ)-3b gives many
side products, which lowers the overall yield to ca. 30%.
Therefore, we decided to use the enzyme-catalyzed reaction
instead of the standard one and to stop it at the very latest
possible stage to achieve almost 100% conversion of
alcohol to ester. In this way, we obtained the desired race-
mic 1-(1H-1,2,4-triazol-1-yl)butan-2-yl acetate [(Ϯ)-4b] with
a very acceptable yield (91%, Table 4).
1
2
3
4
5
6
7
8
Novozym 435[a] 94
46
alcohol 71 19
98
70
53
31
60
39
74
56
80
72
88
91
ester
alcohol 66 48
ester 92
alcohol 73 60
ester 93
alcohol 60 19
ester 82
alcohol 72 17
ester 87
alcohol 98 40
ester 80
82
Amano PS[a]
Amano AK[a]
Amano PS-C[a]
163
163
49
41
43
42
45
52
45
40
Amano PS-IM[b] 16
Amano PS-IM[b] 18
Amano PS-IM[c] 28
Amano PS-IM[d] 40
alcohol 82 Ͼ200 93
ester
alcohol 64 53
ester 93
99
60
70
75
[a] Conditions: (Ϯ)-3a 100 mg, lipase 100 mg, solvent 7.5 mL, acet-
ylating agent 550 mg (5 equiv.). [b] Conditions: (Ϯ)-3a 1 g, lipase
0.3 g, solvent 10 mL, acetylating agent 2.2 g (2 equiv.). [c] Condi-
tions: (Ϯ)-3a 1 g, lipase 0.3 g, solvent 10 mL, acetylating agent
1.65 g (1.5 equiv.). [d] Conditions: (Ϯ)-3a 2 g, lipase 0.3 g, solvent
20 mL, acetylating agent 2.64 g (1.2 equiv.). [e] Based on GC, for
confirmation the % conversion was calculated from the enantio-
meric excess of the starting material (ees) and the product (eep)
according to the formula: conv. = ees/(ees + eep). [f] Determined by
HPLC analysis with a Chiralcel OD-H column. [g] E = ln[(1 –
conv.)(1 – ees)]/ln[(1 – conv.)(1 + ees)].
Table 4. Synthesis of acetylated standard samples (Ϯ)-4a and (Ϯ)-
4b for enzymatic reactions.
Entry Product
Acylating
agent
Solvent
Catalyst
Time Yield
[h]
[%][a]
64
1
2
(Ϯ)-4a
Ac2O
–
pyridine +
DMAP
72
(Ϯ)-4b vinyl acetate 2-methyl- Novozym
2-butanol SP 435
48
91
[a] Isolated yield.
As we had confirmed that the problem of spontaneous
transesterification of racemic (Ϯ)-3b by vinyl acetate does
not exist, we screened three lipase preparations as catalysts
Stereochemistry Determination of Alcohols (+)-5a and (+)-5b
The stereochemical preference of the PS-IM lipase in the
of the reaction with enol esters (vinyl acetate or 1-acetoxy- acetylation reaction of (Ϯ)-3a and (Ϯ)-3b can be deter-
2-methylcyclohexene in 2-methyl-2-butanol, Table 3) to find mined by establishing the absolute configuration of the chi-
the most efficient system. The lipase-catalyzed transesterifi- ral center in the slower reacting enantiomer of imidazolic
cation reaction with vinyl acetate as acyl donor, proceeded alcohol (+)-5a and triazolic alcohol (+)-5b. For these
faster than the reaction with 1-acetoxy-2-methylcyclohex- alcohols, a simple 1H NMR method based on double
ene (Table 3, Entries 6 and 7). All of the lipase-catalyzed derivatization described by Mosher[20] can be applied. We
kinetic resolutions of racemic (Ϯ)-3b yielded enantiomer- achieved this by transformation of the investigated alcohol
ically enriched products with satisfactory ee values that enantiomer [(+)-5a or (+)-5b] into two diastereomeric esters
Table 3. Lipase-catalyzed resolution of (Ϯ)-3b.
Entry
1
Enzyme
Amano PS[a]
Acylating agent
vinyl acetate
t [h] T [°C] Conv.[c] [%]
Product
ee[d] [%]
E[e]
Yield[f] [%]
108
18
17
17
5
r.t.
r.t.
r.t.
r.t.
30
49
51
52
51
48
50
49
alcohol
ester
alcohol
ester
alcohol
ester
alcohol
ester
alcohol
ester
alcohol
ester
alcohol
ester
89
93
96
92
Ͼ 99
94
Ͼ 99
95
92
98
98
83
64
56
68
60
58
53
61
57
92
77
75
66
84
86
2
3
4
5
6
7
Amano AK[a]
vinyl acetate
vinyl acetate
Ͼ100
Ͼ200
Ͼ200
Ͼ200
Ͼ200
91
Amano PS-IM[a]
Amano PS-IM[b] 1-acetoxy-2-methylcyclohexene
Amano PS-IM[a]
Amano PS-IM[a]
vinyl acetate
vinyl acetate
6
30
97
92
93
Amano PS-IM[b] 1-acetoxy-2-methylcyclohexene
9
30
[a] Conditions: (Ϯ)-3b 1 g, lipase 0.3 g, solvent 10 mL, vinyl acetate 3 g (5 equiv.). [b] Conditions: (Ϯ)-3b 1 g, lipase 0.3 g, solvent 5 mL,
1-Acetoxy-2-methylcyclohexene 2.73 g (2.5 equiv.). [c] Based on GC, for confirmation the % conversion was calculated from the enantio-
meric excess of the starting material (ees) and the product (eep) according to the formula: conv. = ees/(ees + eep). [d] Determined by
HPLC analysis with a Chiralcel OD-H column. [e] E = ln[(1 – conv.)(1 – ees)]/ln[(1 – conv.)(1 + ees)]. [f] Isolated yield after column
chromatography.
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Synthesis and Antimicrobial Activity of Chiral Ionic Liquids
Scheme 2. Assignment of the absolute configuration of alcohols (+)-5a and (+)-5b.
Figure 1. Description of substituents for determination of the absolute configuration of (+)-5a and (+)-5b.
by reacting it separately with chiral auxiliary [(R)- and (S)- yl)butan-2-ol (+)-5b were carried out with a few bromo- or
α-methoxy-α-phenylacetic acid (MPA), Scheme 2], followed iodoalkanes. The haloalkane was added in excess to a solu-
by comparison of the 1H NMR spectra of the resulting two tion of (+)-5a or (+)-5b in acetonitrile previously dried with
derivatives of each enantiomer of the alcohol (Figure 2).
molecular sieves (4 Å). The quaternization of the N-3 atom
Taking into consideration the finding[21] that in the α- of imidazole and the N-4 atom of the 1,2,4-triazole ring of
methoxy-α-phenylacetic acid esters of secondary alcohols, the derivatives produced salts (+)-7a–i and (+)-8a–f in
the most representative and energetically favorable (stable) Ͼ 75% and Ͼ 49% isolated yields, respectively (Table 5).
is the sp conformer, and evaluating differences in chemical We noticed that product (+)-7a could only be obtained suc-
shifts of the relevant protons in the MPA-esters, the abso- cessfully in a pressurized reactor because ethyl bromide
lute configuration of the investigated enantiomeric form of presents serious problems of low reactivity and volatility.
both alcohols has been assigned as (S).
All except one of the prepared imidazolium quaternary salts
The results of the equations presented in Figure 1 and an are liquid at room temperature. On the other hand, the tri-
examination of the 1H NMR spectroscopic data of the (R)- azolium salts are solids or very viscous liquids (gums).
and (S)-MPA ester derivatives are consistent with the three-
dimensional structure proposed in Figure 2.
It is easily noticed that if the absolute configuration of
the slower reacting enantiomer of (+)-5a or (+)-5b is (S),
Table 5. Synthesis of chiral imidazolium [(+)-7a–i] and triazolium
the substituents are arranged in such a way that in the (S)-
MPA esters, the imidazole ring H(2Ј) and triazole ring H(5Ј)
protons are shielded by the phenyl ring (owing to the space-
orientated anisotropic effect), whereas the same protons in
the (R)-MPA esters are unaffected. An especially big differ-
ence (δ = 0.99 ppm) of the H(2Ј) proton chemical shifts in
both MPA esters of imidazolium derivatives 10a and 9b is
observed. The opposite effect is found for the aliphatic pro-
tons H(9Ј), which are shielded in (R)-MPA derivatives but
remain unaffected in (S)-MPA. In the course of our study,
it was observed that the lipase-catalyzed kinetic resolution
of (Ϯ)-3a and (Ϯ)-3b fits the Kazlauskas rule,[22] and the
(R)-ester and (S)-alcohol enantiomers are obtained.
[(+)-8a–f] ILs.
Entry
IL
R
X
t
T
Yield M.p. [α]2D9[b]
[h] [°C]
[%]
[°C]
1
2
3
4
5
6
7
8
9
(+)-7a[a] C2H5 Br 24
82
65
65
80
82
82
82
99
99
95
94
94
96
91
88
75
oil
oil
oil
oil
oil
oil
oil
oil
+16.1
+15.2
+14.3
+12.7
+17.3
+17.8
+18.2
+16.4
(+)-7b
(+)-7c
(+)-7d
C3H7 Br 96
C3H5 Br 96
C4H9 Br 96
(+)-7e C5H11 Br 96
(+)-7f C7H15
(+)-7g C10H21
(+)-7h C12H25
(+)-7i C16H33
I
I
I
I
96
96
96 120
96 120
gum +15.9
10
11
12
13
14
15
(+)-8a
(+)-8b
(+)-8c
C3H7 Br 48
C3H5 Br 48
C4H9 Br 48
65
65
80
82
82
82
87
93
49
98
90
77
gum +12.3
gum +11.8
89–90 + 9.7
gum +13.4
81–83 +13.2
gum +12.5
(+)-8d C5H11 Br 48
(+)-8e C7H15
(+)-8f C10H21
I
I
48
48
Synthesis of Chiral Ionic Liquids
The alkylations of optically active (S)-(+)-1-(1H-imid-
[a] Reaction was performed in pressure reactor. [b] Specific rota-
azol-1-yl)butan-2-ol (+)-5a or (S)-(+)-1-(1H-1,2,4-triazol-1- tion; solution in chloroform (c 1.0).
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P. Borowiecki et al.
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Figure 2. The assignment of the absolute configuration of the slower reacting enantiomers (+)-5a (the upper two spectra) and (+)-5b (the
1
lower two spectra) by H NMR spectra and ΔδRS values of the (R)- and (S)-MPA esters.
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Synthesis and Antimicrobial Activity of Chiral Ionic Liquids
Table 6. Growth inhibition halo [cm] for the racemic imidazolium and triazolium ILs (25 mm).
IL
R
E. coli
ATCC
8739
S. typhimurium
ATCC
P. aeruginosa
ATCC
B. subtilis
ATCC
6633
S. aureus
ATCC
6538
C. albicans
ATCC
10231
14028
9027
G(–)
G(–)
G(–)
G(+)
G(+)
yeast
[a]
(Ϯ)-7b
(Ϯ)-7e
(Ϯ)-7f
(Ϯ)-7g
C3H7
C5H11
C7H15
C10H21
–
–
–
–
–
–
–
–
–
–
–
–
1.20Ϯ0.00
1.15Ϯ0.07
1.08Ϯ0.15
0.98Ϯ0.04
1.15Ϯ0.07
1.15Ϯ0.00
1.85Ϯ0.07
1.95Ϯ0.07
2.00Ϯ0.14
1.13Ϯ0.04
1.40Ϯ0.00
–
(Ϯ)-8a
(Ϯ)-8d
(Ϯ)-8e
(Ϯ)-8f
C3H7
C5H11
C7H15
C10H21
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1.15Ϯ0.00
1.20Ϯ0.00
1.15Ϯ0.00
1.05Ϯ0.00
1.58Ϯ0.04
1.40Ϯ0.00
1.20Ϯ0.00
[a] –: no inhibition.
Table 7. The MIC (mm) values for the racemic imidazolium and triazolium ILs.
IL
R
E. coli
ATCC
S. typhimurium
ATCC
P. aeruginosa
ATCC
B. subtilis
ATCC
S. aureus
ATCC
C. albicans
ATCC
8739 G(–)
14028 G(–)
9027 G(–)
6633 G(+)
6538 G(+)
10231 yeast
(Ϯ)-7g
(Ϯ)-7h
(Ϯ)-7i
C10H21
C12H25
C16H33
0.4
0.08
0.4
0.5
0.3
0.8
2.1
1.1
3.8
0.5
0.3
0.5
0.4
0.005
0.3
0.2
0.3
2.7
(Ϯ)-8f
C10H21
1.3
3.3
4.4
3.4
0.6
1.0
Table 8. Antifungal activity (% of control) of the racemic imidazolium and triazolium ILs (1 mm).
IL
R
F. oxysporum F. sambucinum
F. culmorum
MF 18
A. brasiliensis
ATCC 16404
C. coccodis
MC 1
P. infestans
MP 324
P. infestans
MP 1320
MF 5
MF 1
(Ϯ)-7b C3H7
(Ϯ)-7e C5H11
(Ϯ)-7f C7H15
(Ϯ)-7g C10H21
(Ϯ)-7h C12H25
(Ϯ)-7i C16H33
94.12Ϯ3.91
94.65Ϯ6.09
32.99Ϯ1.71
64.12Ϯ3.90
24.54Ϯ1.36
40.89Ϯ2.58
101.14Ϯ3.62
93.51Ϯ3.61
32.13Ϯ2.54
53.82Ϯ19.46
25.39Ϯ0.78
33.59Ϯ0.90
100.40Ϯ0.00
99.12Ϯ2.64
55.42Ϯ3.08
46.71Ϯ2.28
40.21Ϯ2.39
60.14Ϯ7.57
98.44Ϯ3.21
89.96Ϯ3.95
83.95Ϯ2.85
78.93Ϯ2.79
38.94Ϯ15.96
27.63Ϯ0.72
93.91Ϯ6.02
94.24Ϯ3.65
86.55Ϯ3.89
67.98Ϯ3.00
52.16Ϯ1.01
54.90Ϯ4.44
109.29Ϯ5.26 104.32Ϯ10.88
105.05Ϯ9.16
83.85Ϯ1.51
86.22Ϯ5.51
32.21Ϯ27.90
44.11Ϯ13.79
91.41Ϯ2.85
45.95Ϯ4.69
54.55Ϯ1.75
62.86Ϯ3.48
58.43Ϯ13.70
(Ϯ)-8a C3H7
(Ϯ)-8d C5H11
(Ϯ)-8e C7H15
(Ϯ)-8f C10H21
93.77Ϯ1.33
90.12Ϯ3.39
87.76Ϯ5.03
53.73Ϯ4.75
104.56Ϯ1.92
95.42Ϯ4.41
92.37Ϯ3.82
24.12Ϯ2.04
101.21Ϯ0.93
99.56Ϯ2.27
93.17Ϯ1.31
48.03Ϯ0.76
100.78Ϯ0.78
89.12Ϯ1.60
94.03Ϯ1.04
91.19Ϯ3.63
99.57Ϯ3.29
93.83Ϯ1.90
95.09Ϯ1.82
78.95Ϯ0.00
90.51Ϯ3.76
105.05Ϯ2.47
105.38Ϯ1.45
69.29Ϯ0.00
108.39Ϯ2.95
94.29Ϯ20.89
81.15Ϯ0.74
53.41Ϯ3.12
Antimicrobial Activity of Ionic Liquids
of imidazolium ILs seems to be slightly stronger than ac-
tivity of triazolium ILs (Tables 6 and 7). The relationship
between alkyl chain length and antifungal activity of the
tested compounds was less evident, however it could still be
observed (Table 8), which is in keeping with observations
made recently for other filamentous fungi.[24] Notably, the
common feature of the ILs is a dependency of antimicrobial
potency on the length of the carbon substituent, which sug-
gests a general mechanism of action by membrane damage
controlled by the lipophilicity of the cation (i.e., alkyl chain
length).[25]
The antimicrobial and antifungal activities of the synthe-
sized ILs were evaluated against a wide range of microorga-
nisms. The studies were conducted on three strains of gram-
negative bacteria, two strains of gram-positive bacteria, and
eight strains of fungi. For the bacteria and yeasts, we used
an agar diffusion test as a preliminary screening method
(Table 6), which allowed us to select the most promising
compounds for further determination of minimal inhibitory
concentrations (MICs) by
a broth dilution method
(Table 7). The antifungal activity was tested by an agar di-
lution method, and the results are listed in Table 8.
Some of the tested compounds exhibited quite strong ac-
tivity and wide antibacterial and antifungal action. Their
activity was greatly related to the alkyl chain length, which
Conclusions
Lipase-catalyzed transesterification was established as an
is in good agreement with observations made by numerous efficient technique for the kinetic resolution of secondary
studies.[23] The strongest activity was observed in the case alcohols with an imidazole or 1,2,4-triazole ring. The enan-
of imidazolium ILs with an alkyl chain substituent of 12 tiomerically enriched alcohols obtained by this method
carbon atoms (Table 7). Moreover, the antibacterial activity have proven to be valuable synthons for various optically
Eur. J. Org. Chem. 2013, 712–720
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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717

P. Borowiecki et al.
FULL PAPER
q, quartet; m, multiplet; coupling constants (J) are given in Hertz
(Hz). Mass spectra were recorded with a Micro-mass ESI Q-TOF
spectrometer at the Mass Spectrometry Laboratory, Institute of
Biochemistry and Biophysics (IBB), PAN. IR spectra were mea-
sured with a SPECORD M80 spectrometer. Samples were prepared
in nujol. Elemental analyses were performed with a VARIO EL III
(Elementar Analysensysteme GmbH) elemental analyzer.
active room temperature ionic liquids. Interesting observa-
tions were made during the experiments of lipase-catalyzed
acetylation of the racemic alcohol (Ϯ)-3a. We discovered
some unexpected difficulties connected with a spontaneous
transesterification of the alcohol by several acetates. The
observations enabled us to suggest a hypothesis that a
unique autocatalysis mechanism exists, which may be con-
nected to the imidazolium ring of the substrate molecule.
This problem has not been sufficiently considered and still
lacks theoretical explanation although the lipase-catalyzed
separation of the desired alcohol was effectively achieved
by using a nonstandard acylating agent (1-acetoxy-2-meth-
ylcyclohexene). The antibacterial and antifungal activity of
the final imidazolium and triazolium salts was evaluated
by three different methods. Some of the tested compounds
exhibited quite strong biological activity, which was greatly
related to the alkyl chain length. Notably, the imidazolium
salts revealed slightly stronger antibacterial activity than
the triazolium salts.
Preparation of Racemic Alcohols and Esters for Kinetic Enzymatic
Resolution
1-(1H-Imidazol-1-yl)butan-2-ol [(؎)-3a]: A mixture of imidazole
(9.99 g, 146.8 mmol) and 1,2-butylene oxide (10.59 g, 146.8 mmol)
was placed in a round-bottomed flask and stirred at 60 °C for 72 h.
Purification of the resulting crude product by column chromatog-
raphy [CHCl3/MeOH (8:2)] afforded a yellowish oil (20.42 g,
145.67 mmol, yield 99%).
1-(1H-1,2,4-Triazol-1-yl)butan-2-ol [(؎)-3b]: A mixture of 1,2,4-tri-
azole (7 g, 101.4 mmol) and 1,2-butylene oxide (8.77 g,
121.63 mmol) was placed in a round-bottomed flask and stirred at
70 °C for 24 h. The resulting crude product was purified by column
chromatography [CHCl3/MeOH (95:5)] to afford a yellowish oil
(13.78 g, 97.61 mmol, yield 96%).
1-(1H-Imidazol-1-yl)butan-2-yl Acetate [(؎)-4a]: A mixture of pyr-
idine (4.5 mL, 4.38 g, 55.74 mmol), acetic anhydride (0.39 mL,
0.41 g, 4.04 mmol), and DMAP (30 mg) was cooled to 0 °C, and
1-(1H-1,2,4-triazol-1-yl)butan-2-ol (0.54 g; 3.85 mmol) was added.
The mixture was stirred at room temperature for 72 h. The pyridine
was then evaporated under reduced pressure, and the reaction was
quenched with saturated NaHCO3 solution (7.5 mL) and extracted
with AcOEt (3ϫ 5 mL). The organic phases were combined and
condensed by using a rotary evaporator. The residue was dissolved
in toluene (20 mL), and the solvents were evaporated to dryness.
The product was purified by column chromatography [CHCl3/
MeOH (95:5)] to afford a yellowish oil (0.45 g, 2.47 mmol, yield
64%).
Experimental Section
General Details: All commercially available reagents (Aldrich,
Fluka and POCH) were used without further purification. Novo-
zym SP 435 (lipase from Candida antarctica B immobilized on a
macroporous acrylic resin, 10000 U/g), Amano PS (native lipase
from Burkholderia cepacia earlier Pseudomonas cepacia,
Ͼ 23.000 U/g), Amano PS-C (immobilized on ceramic particles),
Amano PS-IM (immobilized on diatomite, 500 U/g), and Amano
AK (native lipase from Pseudomonas fluorescens, 20.000 U/g) were
purchased from Novo Nordisk Co. and Amano Pharmaceutical
Co. and were used without any treatment. Melting points were ob-
tained with an MPA100 Optimelt SRS apparatus. Thin-layer
chromatography was performed with aluminum TLC plates with
Kieselgel 60 F254 silica gel (Merck, 0.2 mm thickness film), and
the compounds were visualized in iodine vapor. Preparative plate
chromatography was performed with PSC-Fertigplatten Kieselgel
60 F254 (20ϫ20 cm with 2 mm thickness layer). The chromato-
graphic analyses (GLC) were performed with an HP Series II 5890
instrument equipped with a flame ionization detector (FID) and
fitted with an HP-50+ (30 m) semipolar column. Helium (2 mL/
min) was used as carrier gas; Tinjector = 280 °C, Tcolumn = 100 °C
(3 min) and 100–280 °C (10 °C/min); retention times (tR) are given
in minutes under these conditions. Column chromatography was
performed with Silica gel 60 (Merck) of 40–63 μm. A mixture of
chloroform/methanol was used as eluent (95:5, 9:1 or 8:2 v/v de-
pending on substance purified). The enantiomeric excesses of the
resulting esters and alcohols were determined by HPLC analysis
with a Shimadzu CTO-10ASV chromatograph equipped with an
STD-20A UV detector and a Chiralcel OD-H (Diacel) chiral col-
umn with mixtures of n-hexane/isopropyl alcohol as mobile phase
in appropriate ratios given in experimental section; flow (f) is given
in mL/min; racemic alcohols and esters were used as standards.
1-(1H-1,2,4-Triazol-1-yl)butan-2-yl Acetate [(؎)-4b]: To a solution
of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol (0.3 g, 2.13 mmol) in 2-
methyl-2-butanol (2.5 mL), vinyl acetate (0.91 g, 10.62 mmol,
0.98 mL) and Novozym SP 435 (0.1 g) were added. The reaction
mixture was stirred at room temperature with a magnetic stirrer for
48 h. Aliquots were regularly analyzed by GC until almost 100%
conversion was reached. The enzyme was removed by filtration,
and the solution was evaporated to dryness. The crude product was
purified by flash chromatography with gradient elution [CHCl3/
MeOH (9:1 to 8:2)] to afford a colorless oil (0.35 g, 1.93 mmol,
yield 91%).
1-Acetoxy-2-methylcyclohexene[19] (9): A solution of 2-methylcyclo-
hexanone (30 g, 267.5 mmol, 32.5 mL) in CCl4 (146 mL) was co-
oled to 0 °C. Acetic anhydride (54.6 g, 534.9 mmol, 50.56 mL) and
a catalytic amount of aqueous HClO4 solution (60%) were added,
and the mixture was stirred at room temperature for 24 h. The flask
content was diluted with Et2O (250 mL), washed with saturated
NaHCO3 aqueous solution (3ϫ 200 mL), and the organic phases
were combined and dried with anhydrous Na2SO4. After filtration
and solvent evaporation under reduced pressure, the residue was
purified by vacuum distillation to give a colorless oil (30.4 g,
197.2 mmol, yield 74%, bp 28–28.5 °C, p = 0.05 Torr).
Optical rotations were measured with
a P20 polarimeter
(Belligham & Stanley Ltd., line D spectrum of sodium) in a 2 dm
long cuvette. UV spectra were measured with a Cary 3 spectrome-
1
ter. H and 13C NMR spectra were measured with a Varian Mer-
Kinetic Resolution
cury 400BB spectrometer operating at 400 MHz for 1H and
100 MHz for 13C nuclei; chemical shifts (δ) are given in parts per
million (ppm) relative to tetramethylsilane (TMS) as internal stan-
dard; signal multiplicity assignment: s, singlet; d, doublet; t, triplet;
Lipase-Catalyzed Kinetic Resolution of Racemic (؎)-1-(1H-Imid-
azol-1-yl)butan-2-ol [(؎)-3a]: Racemic 1-(1H-imidazol-1-yl)butan-
2-ol (1 g, 7.13 mmol) was dissolved in 2-methyl-2-butanol (10 mL).
718
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 712–720

Synthesis and Antimicrobial Activity of Chiral Ionic Liquids
Amano PS-IM lipase (0.3 g, 150 U) and 1-acetoxy-2-methylcy-
clohexen (2.2 g, 14.26 mmol) were added. The reaction mixture was
agitated (250 rpm) at room temperature. Aliquots were regularly
analyzed by GC until ca. 52% conversion was reached. The enzyme
was removed by filtration and rinsed with 2-methyl-2-butanol
(15 mL), and the solutions were concentrated under reduced pres-
sure. The products were separated by flash chromatography
[CHCl3/MeOH (9:1)] to afford (S)-(+)-1-(1H-imidazol-1-yl)butan-
2-ol (+)-5a [440 mg, 88% isolated yield; ee = 98%. [α]2D9 = +25.1 (c
= 1.0, CHCl3)] and (R)-(+)-1-(1H-imidazol-1-yl)butan-2-yl acetate
(+)-6a [590 mg, 91% isolated yield; ee = 80%. [α]2D9 = +12.3 (c =
1.0, CHCl3)]. For additional data, see Table 2.
roform/methanol (8:2) mixture as the eluent. The reaction mixture
was cooled to room temperature, and the separated salt was washed
with Et2O (3ϫ 5 mL) to afford a dark oil, which was sequentially
purified from tars with a column filled with active carbon. The
resulting product was a colored oil.
Synthesis of Optically Active Triazolium Salts (+)-8a–f: Optically
active
(S)-(+)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
(0.5 g,
3.54 mmol) was dissolved in dry CH3CN (5 mL), and a threefold
molar excess of the appropriate freshly distilled alkyl bromide or
iodide was added. The reaction mixture was stirred under the con-
ditions given in Table 5. The reaction progress was monitored by
TLC with a chloroform/methanol mixture (8:2) as eluent. The reac-
tion mixture was cooled to room temperature, and the resulting
precipitate was removed by filtration and washed with Et2O (5ϫ
5 mL). The solvent was removed under reduced pressure to yield
the product as a solid or colored sticky oil.
Lipase-Catalyzed Kinetic Resolution of Racemic (؎)-1-(1H-1,2,4-
Triazol-1-yl)butan-2-ol [(؎)-3b]: Racemic 1-(1H-1,2,4-triazol-1-yl)
butan-2-ol (1 g, 7 mmol) was dissolved in 2-methyl-2-butanol
(5 mL). Amano PS-IM lipase (0.3 g, 150 U) and 1-acetoxy-2-meth-
ylcyclohexene (2.73 g, 17.7 mmol) were added. The reaction mix-
ture was agitated at room temperature at 250 rpm. Aliquots were
regularly analyzed by GC until approximately 51% conversion was
reached. The reaction was stopped by removing the catalyst by fil-
tration. The enzyme was washed with 2-methyl-2-butanol (8 mL)
and methanol (5 mL), and the combined solutions were evaporated
to dryness. The products were separated by flash chromatography
[CHCl3/MeOH (95:5)] to afford (S)-(+)-1-(1H-1,2,4-triazol-1-yl)-
Microorganisms Used: The strains of the American Type Culture
Collection (ATCC): Escherichia coli ATCC 8739, Salmonella typhi-
murium ATCC 14028, Pseudomonas aeruginosa ATCC 9027, Bacil-
lus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538, Can-
dida albicans ATCC 10231, Aspergillus brasiliensis ATCC 16404.
The strains received from the IHAR-PIB collection of Plant Breed-
ing and Acclimatization Institute, Młochów: Colletotrichum
coccodis MC 1, Fusarium culmorum MF 18, Fusarium oxysporum
MF 5, Fusarium sambucinum MF 1, Phytophthora infestans MP
324, Phytophthora infestans MP 1320.
butan-2-ol (+)-5b [305 mg, 61% isolated yield; ee Ͼ 99%. [α]2D9
=
+48 (c = 1.0, CHCl3)] and (R)-(+)-1-(1H-1,2,4-triazol-1-yl)butan-
2-yl acetate (+)-6b [370 mg, 57% isolated yield; ee = 95%. [α]2D9
+23 (c = 1.0, CHCl3)]. For additional data, see Table 3.
=
Antimicrobal Activity Assays: A qualitative evaluation of antimicro-
bal activity was determined by the agar diffusion method of Rebros
et al.[26] with some modifications. Bacterial lawns were grown in
liquid tryptic soy broth (TSB, Merck) medium for 24 h. Inocula
of approximately 2.5–3.5ϫ108 CFU/mL (200 μL, CFU = colony
forming unit) were spread on solid tryptic soy agar (TSA, Merck)
medium. Subsequently, sterile 8 mm paper discs were placed on the
surface of the agar, and the IL (20 μL, 0.025 m) was added. The
plates were incubated for 24 h at 30 °C and the diameter of the
growth inhibition zones were measured to the nearest millimeter.
Each test was performed in duplicate. The ILs used in the experi-
ment were diluted with 0.1–1% of EtOH. It was verified in a sepa-
rate experiment that EtOH at a concentration of 0.1–1% did not
inhibit bacterial growth by itself (data not shown).
General Procedure for Determination of the Absolute Configuration
of (+)-5a and (+)-5b
Esterification of (S)-(+)-1-(1H-imidazol-1-yl)butan-2-ol [(+)-5a]
with (R)- or (S)-α-Methoxy-α-phenylacetic Acid: To a solution of
(S)-(+)-1-(1H-imidazol-1-yl)butan-2-ol (50 mg, 0.36 mmol), a cata-
lytic amount of DMAP (5 mg), (R)- or (S)-α-methoxy-α-phenyl-
acetic acid (59 mg, 0.36 mmol), and N,NЈ-dicyclohexylcarbodi-
imide (DCC, 88 mg, 0.43 mmol) in dry CH2Cl2 (2.5 mL) were
added. After 24 h of stirring at room temp., precipitated dicyclo-
hexylurea was removed by filtration and the urea cake was rinsed
with toluene (3ϫ 5 mL). The combined solutions were evaporated,
and the product was purified on a preparative chromatographic
plate with a mixture of hexane/ethyl acetate (1:1) as the eluent.
A quantitative evaluation of antimicrobal activity was determined
by the tube dilution method.[27] Bacterial and yeast strains were
cultured for 24 h on TSB (Merck) medium. The ILs were diluted
in TSB medium and subsequently the same amount of inoculum
was added to each tube. A positive control was prepared without
ILs. The growth (or lack thereof) of the microorganisms was deter-
mined visually after incubation for 24 h at 30 °C. The lowest con-
centration at which there was no visible growth (turbidity) was
taken as the minimal inhibitory concentration (MIC).
Esterification of (S)-(+)-1-(1H-1,2,4-Triazol-1-yl)butan-2-ol [(+)-5b]
with (R)- or (S)-α-Methoxy-α-phenylacetic Acid: A catalytic amount
of DMAP (5 mg) and DCC (87.7 mg, 0.42 mmol) were added to a
solution of (S)-(+)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (50 mg,
0.35 mmol) and (R)- or (S)-α-methoxy-α-phenylacetic acid (59 mg,
0.35 mmol) in dry CH2Cl2 (2.5 mL). After 24 h of stirring at room
temp., precipitated dicyclohexylurea was removed by filtration, and
the urea cake was rinsed with toluene (3ϫ 1.5 mL). The combined
solutions were washed with cold HCl (1 m, 2ϫ 1 mL), saturated
NaHCO3 (2ϫ 1 mL), and saturated NaCl (1 mL). After drying the
solution over anhydrous MgSO4 and evaporation of the solvent,
the product was purified on a preparative chromatographic plate
with a mixture of hexane/ethyl acetate (1:1) as the eluent.
The antifungal activity was evaluated by measuring the inhibition
of radial growth on an agar medium in a petri dish (Liu et al.).[28]
The ILs were dissolved in EtOH (96%). Subsequently, the appro-
priate diluted ILs were added to a potato dextrose agar (PDA,
Merck) medium or in the case of P. infestans strains to a rye agar[29]
medium to give a final concentration of 1 mm of IL and less than
0.1% of ethanol. The 8 mm disks were cut from an actively growing
mycelium of the fungi and placed in the center of the agar plate
containing the proper dilution of IL. The positive control was pre-
pared without IL. The radial growth of the fungal colonies was
measured after several days of incubation at 25 °C (18 °C for the
P. infestans strains). The inhibitory activity of the ILs was expressed
as a percentage of the positive control growth. Each experiment
General Methods for the Preparation of Chiral Ionic Liquids
Synthesis of Optically Active Imidazolium Salts (+)-7a–i: (S)-(+)-1-
(1H-Imidazol-1-yl)butan-2-ol (0.5 g, 3.57 mmol) was dissolved in
dry CH3CN (5 mL) and subsequently a threefold molar excess of
the appropriate freshly distilled alkyl bromide or iodide was added.
The reaction mixture was stirred under the conditions given in
Table 5. The reaction progress was monitored by TLC with a chlo-
Eur. J. Org. Chem. 2013, 712–720
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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719

P. Borowiecki et al.
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Acknowledgments
The project was cofinanced by The European Regional Develop-
ment Fund (grant number POIG.01.03.01-00-158/09; Innovative
Economy Operational Programme 2007–2013: Biotransformations
for Pharmaceutical and Cosmetic Industry). These studies were
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