Journal of Saudi Chemical Society (2020) 24, 631–635

King Saud University

Journal of Saudi Chemical Society

www.ksu.edu.sa
www.sciencedirect.com

ORIGINAL ARTICLE

An efficient preparation and characterization of

1-(2-ethoxy-2-oxoethyl)imidazolium based ionic
liquids derivatives as potential bioactive agents
Bakhet A. Alqurashy

Department of Basic Science and Technologies, Community Faculty, Taibah University, 30002 Al-Madina Al Mounawara,
Saudi Arabia

Received 15 May 2020; revised 19 June 2020; accepted 27 June 2020

Available online 4 July 2020

KEYWORDS Abstract A set of new 1-(2-ethoxy-2-oxoethyl)imidazolium-based ionic liquids (1–16) have been
Imidazolium; prepared via the alkylation reaction of ethyl 2-(1H-imidazol-1-yl)acetate with various type of sub-
Ionic liquids; stituted alkyl halides using a microwave irradiation reaction in yields above 90%. The chemical
Antibacterial activity; structures of the manufactured ILs (1–16) were analyzed by mass and NMR spectroscopy. The
Antifungal activity; newly prepared ILs were examined for their in vitro anti-microbial activities towards different types
Microwave irradiation of Gram (+) and Gram ( ) bacteria, and also for their antifungal activities. The preliminary tests
showed that most of the resultant ILs presented modest activities towards S. aureus and B. subtilis
with IZ values ranging between 10 and 14 mm, while the E. coli activities was in the range of 16 and
20 mm. However, ILs (1–16) displayed poor activities against the C. albicans.
Ó 2020 The Author. Published by Elsevier B.V. on behalf of King Saud University. This is an open access
article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

1. Introduction organic/inorganic anions such as CF3COO , BF4 and PF6

[2,4–6]. One of the important characteristics receiving interest
Ionic liquids (ILs) have established a huge attention and wide- in ionic liquid research is the limitless number of cation/anion
spread use in different areas of chemistry science since the first combinations that leads to a more possibility for tuning chem-
report of ILs (ethylmethylimidazolium tetrafluoroborate) in ical structures and properties. These combinations of anions
1992 by Wilkes et al [1–3]. ILs are salts that possess a reduced and cations help avoiding the form of crystal packing, decrease
melting point (less than 100 °C). This kind of salts are mainly the interionic interaction and hence remain liquid [4,7].
composed of nitrogen-containing bulky organic cations such ILs applications display promising advantages compared to
as N-alkylpyridinium and 1,3-dialkylimidazolium and the conventional volatile organic solvents such as large liq-
uidus range temperature, decent thermal stability, negligible
E-mail address: Bqourasy@taibahu.edu.sa vapor pressure, dissolving polar and non-polar molecules.
Peer review under responsibility of King Saud University. High viscosity is the critical obstacles to ILs applications when
compared to organic solvents, as it decreases the diffusion rate
of the oxidation/reduction species and it also reduces the syn-
thetic organic reaction rate. Consequently, searching for low
Production and hosting by Elsevier viscosity ionic liquids is required [5,8–10]. The physiochemical
https://doi.org/10.1016/j.jscs.2020.06.005
1319-6103 Ó 2020 The Author. Published by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
632 B.A. Alqurashy

characteristics of ILs like polarity, melting point, density and materials) was the evidence of the accomplishment of the reac-
viscosity can be largely tuned through an appropriate choice tion. The produced viscous IL was purified and isolated
of cations and/or anions as well as the type and length of through washing with 10 ml of ethyl acetate (3 times) in order
the alkyl chains [6,7,11,12]. to remove any unreacted starting materials and solvent.
ILs have been intensively used in inorganic synthesis [13], Finally, the target IL was dried at a reduced pressure to
catalysis [14–16], battery [17–19], solar cells [20] and electro- remove all remaining volatile organic compounds.
chemical [21,22] applications. Researchers have investigated
antimicrobial activities of different type of ionic liquids, 2.2.2. Anion metathesis reaction of ILs (5–16)
including phosphonium, quinoliunium, imidazolium, pyri- In a Teflon closed reactor vessel, 1 eq of the imidazolium-
dinium and pyrrolidinium coupled with different anions, halides salts (1–4) was reacted with 1 eq of NaBF4, KPF6 or
towards fungi, biofilm-forming bacteria, gram-negative, CF3CO2Na in DCM. The reaction was left for 10 min under
gram-positive bacteria and enzymes [23–26]. The asymmetric MW irradiation at 80 °C and under 300 W. The ILs (5–16)
1-alkyl-3-methylimidazolium cations paired with small inor- were collected as outlined in the conventional method. The
ganic anions are the most widely studied ILs. It has been noted subsequent product was then filtered, and the solvent was
that biological activities are little affected by the nature of removed to afford the desired ILs (6–20).
anions but are largely influenced by surfactant properties of
imidazolium based ionic liquids such as the length of the alkyl 3. Results and discussion
side chain. 1-alkyl-3-methylimidazolium based ionic liquids
exhibited excellent anti-biofilm activity towards pathogen
micro-organisms. Consequently, ionic liquids can be an appro- In this study, sixteen imidazolium salts were prepared by vary-
priate choice for more development of novel antimicrobial ing the functional groups of the alkyl substituents as well as the
agents for different applications [27–30]. anion units to investigate the impact of these salts on the bio-
Nowadays, the application of microwave-assisted green logical activities. The quaternization reaction of ethyl 2-(1H-
technique is necessity for synthetic chemistry community; as imidazol-1-yl)acetate with variant type of alkyl halides con-
this technique offers several advantages over the traditional taining an ester, ether or an alcohol functional group, in
methods including eco-friendly, accelerating reaction times toluene were carried out by using microwave irradiation
and increasing yields. The alteration of anions in the prepara- (MW) technique afforded the desired 1-(2-ethoxy-2-oxoethyl)
tion of ionic liquids is a topic of interest in order to assess their imidazolium halide salts (1–4) as shown in Scheme 1. The
impacts [31–33]. The aim of this paper is to prepare a new set microwave reaction conditions were optimized by using either
of 1-(2-ethoxy-2-oxoethyl)imidazolium-based ionic liquids temperature or power control.
derivatives using microwave-assisted technique. Additionally, The produced ILs (1–4) were collected as yellow viscous oils
the newly prepared room temperature ionic liquids were in yields above 90% (see Table 1). 1-(2-Ethoxy-2-oxoethyl)-3-
assessed for their antifungal and antibacterial activities in (3-phenoxypropyl)-1H-imidazol-3-ium bromide (1) is used as
order to recognize the association between their structures the reference ionic liquid so as to highlight the spectroscopic
and toxicities. data of the all prepared ILs (1–4).
The 1H NMR chemical shifts of the compound 1 showed
protons of NCH2CH2CH2OPh as quintet at 2.28 ppm, and tri-
2. Experimental
plet at 3.96 ppm for CH2CH2OPh and as a triplet at 4.55 ppm
for NCH2CH2. The NMR spectrum also displayed singlet,
2.1. Material and apparatus
quartet and triplet signals at 5.29, 4.12 and 1.17 ppm for the
attached ethyl acetate group. The triplet, triplet and doublet
All chemicals were bought from commercial suppliers and peaks located at the aromatic region at 7.20, 6.87 and
used without any purification. 1H, 13C, 13C-DEPT, 19F, 11B 6.80 ppm are assigned to the phenyl ring (OPh); where those
and 31P nuclear magnetic resonance (NMR) were recorded at appeared at 10.34 and 7.54 ppm are referred to the protons
RT on a Bruker AV 400 (400 MHz) using DMSO d6. A Bruker of the imidazolium system. The 1H NMR chemical shifts of
Maldi TOF MS was applied to record mass spectra. CHNS IL 2 showed similar feature to that of IL 1, however, an addi-
analyses were recorded using the 2400 Series II CHNS/O ana- tional quintet peak is appeared IL 2 at 1.70 ppm for the extra
lyzer. A controllable single-mode microwave reactor, CEM methylene group. The 1H NMR spectrum of IL 3 showed two
Discovery, was used for the microwave-assisted reactions. triplet peaks for NCH2CH2OH. Lastly, the 1H NMR of IL 4
The reactor is facilitated with a plethora of pressure, a mag- presented a singlet peak at 4.53 ppm for NCH2Ph.
netic stirrer and a control of temperature and power. The 13C NMR spectrum were consistent with the prepared
ILs (1–4). For IL 1, a CH3 group peak appeared at 14.0 ppm
2.2. Synthesis and five CH2 peaks appeared at 25.4, 48.9 50.2, 52.9 and
63.1 ppm. Peaks placed at the aromatic region from 121.0 to
2.2.1. Preparation of ethyl 2-(1H-imidazol-1-yl)acetate halides 137.0 ppm are referred to the carbons on the phenyl and imi-
(1–4) dazolium rings, where the peak appeared at 160.1 ppm is to the
In a Teflon closed reaction vial, 1 eq of an appropriate alkyl C‚O group. 13C-DEPT-NMR was also applied in order to
halide and 1 eq of ethyl 2-(1H-imidazol-1-yl)acetate were prove the formation of the resultant ILs.
added together in toluene. Then, the reaction was subjected The subsequent step involved the preparation of the wanted
to irradiation for 20 min at 80 °C under power of 300 W. ILs (5–16) by varying the counter anion of (1–4) using an
The formation of two phases (IL which is not soluble in aqueous solution of potassium hexafluorophosphate (KPF6),
toluene and the organic phase containing unreacted starting sodium tetrafluoroborate (NaBF4) or sodium trifluoroacetate
An efficient preparation and characterization of 1-(2-ethoxy-2-oxoethyl)imidazolium 633

Scheme 1 Chemical structures of ethyl 2-(1H-imidazol-1-yl)acetate-based ILs (1–4).

Table 1 Yields of the prepared ILs (1–4) under MW. Table 2 Yields of the prepared ILs (5–16) under MW.
Compound RBr Yield (%) ILs cation R Anions Yield (%)
1 Br(CH2)3OPh 91 5 (CH2)3OPh NaBF4 96
2 Br(CH2)4OPh 93 6 KPF6 95
3 Br(CH2)2OH 92 7 CF3COONa 98
4 ClCH2(2-Cl)-Ph 90
8 (CH2)4OPh NaBF4 95
9 KPF6 97
10 CF3COONa 96
(CF3COONa) as shown in (Scheme 2). 1H, 13C, 13C-DEPT, 11 (CH2)2OH NaBF4 98
31
P, 11B, 19F NMR and LCMS were applied to verify the 12 KPF6 97
development of the resultant ionic liquids. NMR spectroscopy 13 CF3COONa 96
was the crucial technique in determining the success of the 14 (2-Cl)-PhCH2 NaBF4 99
anions exchange metathesis reactions. 15 KPF6 96
Anion exchanging reaction from Br or Cl to PF6 , 16 CF3COONa 96
CF3CO2 or BF4 demonstrated a slight shift in the NMR spec-
trum. 11B, 19F and 31P NMR chemical shifts proved the
accomplishment of the anions exchange metathesis reactions.
The resultant ILs (5–16) were afforded as yellow viscous oils 3.1. Antibacterial and antifungal activity
in high yields above 90% (see Table 2). NMR data of the pre-
pared ionic liquids (1–16) are presented in the experimental To examine the ionic liquids as antibacterial agents owing to
section. All prepared ILs in this study (1–16) were examined the existence of a nitrogen-containing five-membered imida-
for biological activities to assert the properties of antibacterial zole ring, ester group and ether-functionalized aromatic ring,
and antifungal activity. the newly prepared ILs (1–16) were screened for their

Scheme 2 Anion metathesis reactions using MW conditions: (i) DCM, 80 °C, 10 min, MY (M = Na, K.)
634 B.A. Alqurashy

Table 3 Antibacterial and antifungal activities (inhibition zone; diameter in mm) of ILs 1–16.
ILs Antibacterial activity Antifungal activity
Gram (+) Gram ( )
S. aureus B. subtilis E. coli C. albicans
1 12 12 20 6
2 11 14 18 8
3 12 – 17 7
4 12 10 – 8
5 11 – 19 –
6 – 11 20 7
7 10 10 19 6
8 12 12 – 8
9 – 11 18 6
10 15 12 – 7
11 10 – 18 6
12 11 11 16 7
13 – 12 16 –
14 11 10 – 6
15 10 12 17 –
16 10 – 18 8
Gentamycin 24 26 30 –
Ketoconazole – – – 20

in vitro antibacterial activities towards human pathogenic S. ILs (1–16) offered relatively weak activities (ranging between
aureus and B. subtilis (Gram-positive) and also towards 6 and 8 mg/mL) against the C. albicans bacterial strains, while
E. coli (Gram-negative) bacterial strains using the diffusion they displayed relatively good activities towards E. coli, S. aur-
agar disc technique. It is obvious from the inhibition zone eus and B. subtilis.
(IZ) results of the all tested ILs (1–16) summarized in Table 3
that the majority of them presented modest activities against Declaration of Competing Interest
the growth of the majority of selected strains compared with
the standards Ketoconazole and Gentamicin. The authors declare that they have no known competing
Furthermore, the results also clearly showed that all tested financial interests or personal relationships that could have
ILs (1–16) possessed a moderate towards S. aureus and B. sub- appeared to influence the work reported in this paper.
tilis with the inhibition zone (IZ) results fluctuating between 10
and 14 mm. Also, the resultant ILs, except 4, 8, 11 and 16, dis- Appendix A. Supplementary data
played good activities against E. coli bacterial strains (in the
range of 16 and 20 mm) relative to the standard gentamycin.
Supplementary data to this article can be found online at
On the other hand, the antifungal activities of all ILs (1–16)
https://doi.org/10.1016/j.jscs.2020.06.005.
were evaluated using also the diffusion agar disc technique.
All ILs, except 5, 13 and 15, exhibited relatively weak activities
towards the C. albicans bacterial strain (ranging between 6 and References
8 mm) relative to the standard ketoconazole. These modest
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