Synthesis of novel proline-based imidazolium ionic liquids

Article abstract of DOI:10.1007/s00706-020-02670-x

Abstract: A series of eight novel proline functionalized dipeptide imidazolium ionic liquids (DPILs), i.e. Boc-[Pro-Pro-EMIM], Boc-[Pro-Val-EMIM], Boc-[Pro-Ala-EMIM], Boc-[Pro-Phe-EMIM] containing [Cl] and [NTf₂] anions were synthesized via a f

Full text of DOI:10.1007/s00706-020-02670-x

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-020-02670-x
ORIGINAL PAPER
Synthesis of novel proline‑based imidazolium ionic liquids
Snehkrishn A. Chaubey1 · Niranjan Patra1 · Roli Mishra1
Received: 28 April 2020 / Accepted: 10 August 2020
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
A series of eight novel proline functionalized dipeptide imidazolium ionic liquids (DPILs), i.e. Boc-[Pro-Pro-EMIM], Boc-
[Pro-Val-EMIM], Boc-[Pro-Ala-EMIM], Boc-[Pro-Phe-EMIM] containing [Cl] and [NTf2] anions were synthesized via a
facile reaction of 2-chloroethylamine with four diferent dipeptides (Boc-Pro-Pro-OH, Boc-Pro-Val-OH, Boc-Pro-Ala-OH,
and Boc-Pro-Phe-OH) followed by reaction with 1-methylimidazole and subsequent anion exchange. The synthesized ILs
revealed similar characteristics of a conventional imidazolium ILs. The synthesized ILs were investigated by 1H NMR, 13
C
NMR, FT-IR, mass spectroscopy, TGA, and DSC. TGA revealed an improved thermal stability for NTf2 over chloride ion.
DSC revealed a melting temperature less than 100 °C.
Graphic abstract
Boc-[Pro-AA-EMIM][Cl]/NTf2
]
Cation
O
H
N
A
A
Boc
N
N
Anion
Cl
NTf2
N
N
H
O
AA = Proline
Valine
Alanine
Phenyl Alanine
Keywords Proline · Dipeptide ionic liquids · Imidazolium · Amino acid-based ionic liquids · Physicochemical properties
Introduction
sensors, super capacitors, biocatalytic reactions, biosensors,
bio preservation as well as protein solubilization, stabiliza-
tion and crystallization [6], miscibility with water and/or
organic solvents [7], melting point [8–12]. AAILs have also
been shown to have excellent CO2 absorption and membrane
transport properties [13–18].
Amino acid-based ionic liquids (AAILs) have drawn tre-
mendous attention of researchers due to their potential
structural and biocompatible properties [1–5]. Amino acids
(AAs) can be easily converted into cations and anions in
ILs since they have side chains/functional groups as well
as chiral properties which can defne their wide range of
physicochemical and biological properties. These properties
make them suitable to fnd applications as electrochemical
There are quite a few reports in which amino acids
have been used as cations [19]. Amino acids and their
ester salts [AAE] [NO3/Sac] based ionic liquids have
been reported by Kou et al. [20]. In most cases, synthe-
sized AAILs and amino acids are used as anions [21, 22].
Various imidazolium-based AAILs have been synthesized
using 20 natural amino acids and imidazole. All the syn-
thesized [EMIM][AA] ILs are stable up to 200 °C except
the [EMIM][CYS]. Recently, AAILs with amino acids as
the anions and phosphonium, choline, ammonium, and
imidazolium as the cations have been reported [23, 24] to
have interesting physicochemical and biological activities.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-020-02670-x) contains
supplementary material, which is available to authorized users.
* Roli Mishra
roli.mishra@iar.ac.in; rolimishra2@gmail.com
1
Department of Engineering and Physical Sciences, Institute
of Advanced Research, Gandhinagar 382426, India
Vol.:(0123456789)
1 3

S. A. Chaubey et al.
Subsequently, several other amino acid-based ILs have
been synthesized such as glycine-based ILs [25], N-heter-
ocyclic amino acid-derived ILs [26], valine, leucine, and
alanine-based chiral imidazolium ILs [27], 4-HO-Pro-Val
tagged 1-methylimidazolium ionic liquids as catalyst for
asymmetric aldol reactions [28]. Amino acid choline-based
ionic liquids (AACBILs), i.e. choline alanine ([CH][Ala]),
choline β-alanine ([CH][β-Ala]), and choline phenyla-
lanine ([CH][Phe]) were explored using the quantum
mechanical calculations and also molecular dynamics
simulations in both gas and liquid phases [29]. The prop-
erties of the [EMIM][GLY] ionic liquid with respect to
fullerenes, graphene, and carbon nanotubes were studied
using molecular dynamics simulations [30]. Amino acid
(AAs) based ionic liquids (ILs) containing amino acids as
anions, namely [TMA][AA] and [TBP][AA] showed good
CO2 absorption activity [31].
Results and discussion
Syntheses of dipeptide-based imidazolium ionic liquids were
carried out as shown in Schemes 1 and 2. Boc-Pro-OH was
coupled with H-Pro-OMe.HCl/H-Val-OMe HCl/H-Ala-
OMe.HCl/H-Phe-OMe.HCl using ethyl chloroformate. The
resulting dipeptides were hydrolyzed with NaOH to produce
dipeptides 6–9 with free carboxylic acid (Scheme 1).
Subsequently these peptides 6–9 with free carboxylic
acid were coupled with chloroethylamine hydrochlo-
ride using ethyl chloroformate and triethylamine to yield
2-chloroethylamide containing dipeptides Boc-Pro-Pro-
2-chloroethylamide, Boc-Pro-Pro-2-chloroethylamide,
Boc-Pro-Val-2-chloroethylamide, Boc-Pro-Ala-2-chlo-
roethylamide (10–13), respectively. Quaternization of
1-methylimidazole with Boc-Pro-Pro-2-chloroethylamide,
Boc-Pro-Pro-2-chloroethylamide, Boc-Pro-Val-2-chloro-
ethylamide, Boc-Pro-Ala-2-chloroethylamide (10–13) fur-
nished Boc-[Pro-Pro-EMIM][Cl]/Boc-[Pro-Val-EMIM]-
[Cl]/Boc-[Pro-Ala-EMIM][Cl]/Boc-[Pro-Phe-EMIM][Cl]
(14–17, Scheme 2). Then, the halide ion of these salts was
exchanged with LiNTf2 (trifuoromethanesulfonimide lith-
ium salt) to yield dipeptide-based imidazolium ionic liquids
with NTf2 anion 18–21 (Scheme 2).
Presently the most commonly used amino acid-based
ionic liquids contain amino acids as anions. There is lim-
ited evidence of amino acid-based ionic liquids where
amino acids are used as cations instead of anions. Amino
acid-based ionic liquids with l-proline as cations have
been reported as chiral separation ligands [32]. Further,
Xiao et al. synthesized poly-l-cysteine-bearing imidazo-
lium salts; Hu et al. presented l-glutamate-based poly-
peptide ILs; while Guillen et al. depicted (S)-histidine-
bearing imidazolium ILs [33–35]. l-Valine-based alkyl
chain-appended 1,2,3-triazolium room temperature chiral
ILs (CILs) with iodide and hexafuorophosphate anions
were synthesized and characterized [36]. The longer alkyl
chain containing CILs displayed facile self-aggregation,
whereas both short and long alkyl chains containing CILs
showed pre-micellar aggregation. Herein, we report a fac-
ile approach to synthesize a novel peptide-based imidazo-
lium ILs in which peptides are present as cations. These
peptide-based imidazolium ILs exhibit improved thermal
and structural properties. To the best of our knowledge,
this is the frst report of synthesis on proline-based dipep-
tide imidazolium ILs.
The structure and purity of the synthesized DPILs
1
were confirmed with H NMR, 13C NMR, FT-IR, and
ESI spectroscopy. FT-IR spectra of the DPILs exhibited a
characteristic absorption band for amide N–H symmetric
stretching around at 3320–3255 cm−1. The aliphatic –CH2
and –CH3 (aliphatic C–H stretching) bands appeared at
2837–2950 cm−1 region. The presence of the amide car-
bonyl group (CO–NH) was indicated by a strong band at
1643 cm−1. The presence of C–N bond stretching in the
region of 1165–1249 cm−1 was due to the formation of
quaternary nitrogen of imidazole ring while peaks at 1643,
1563 cm−1 were due to –C = N bond of five-membered
imidazolium ring. Additionally, the peaks at 1417 cm−1
were due to –C = C– bond and imidazolium ring. In IR
spectrum of DPILs 18–21 with anion [NTf2], the band at
Scheme 1
Cl–
OCH3
O
i. Et3N, ClCO2Et, 6 h, 78%
N+
H2
N
+
N
N
O
ii. LiOH (2 N), MeOH, 4 h, rt
Boc
OH
Boc
O
O
O
H
2
Proline-OMe ( )
6
Boc-Pro-Pro-OH ( )
N-
Boc-proline-OH
3
Valine-OMe ( )
7
Boc-Pro-Val-OH ( )
4
Alanine-OMe ( )
1
( )
8
Boc-Pro-Ala-OH ( )
5
Phenylalanine-OMe ( )
9
Boc-Pro-Phe-OH ( )
1 3

Synthesis of novel proline-based imidazolium ionic liquids
Scheme 2
O
O
H
N
Cl
Cl
N
N
H
N
N
Cl
Boc
Boc
O
O
O
O
N
H
O
10
11
Cl(CH2)2 NH2.HCl
Boc-Pro-AA-OH
H
N
O
Et3N, ClCO2Et,
0 °C, 8 h, 88%
H
N
H
N
6-9
Cl
N
N
H
N
AA = Proline/
Valine/
Boc
Boc
Alanine/
Phenylalanine
13
12
i. Acetonitrile, 70 °C
ii.
N
N
O
H
N+
N+
N
N
N
N
N
N
H
N
Boc
O
N
H
Cl–
Boc
O
O
Cl–
15
14
O
N+
O
H
N+
H
N
H
N
N
N
N
N
H
N
N
Cl–
Boc
Boc
O
Cl–
O
17
16
CH3OH
LiNTf2
O
H
N
N+
N
N+
N
N
N
H
N
N
Boc
Boc
O
O
-
N
H
NTf2
O
-
NTf2
19
18
O
N+
O
H
N
N+
H
N
H
N
N
N
N
H
N
N
-
Boc
Boc
O
-
O
NTf2
NTf2
21
20
1120–1470 cm−1 corresponds to the SO2 symmetric, CF3
and SO2 asymmetric stretching vibrations.
a multiplet in the range of 8.95–9.23 ppm for compound 14,
9.2–9.12 ppm for DPILs 15, 16, and 9.08–9.25 for DPIL 17.
For DPIL 17, the fve aromatic protons appeared as multiplet
in the range of 7.76–7.17 ppm. The 9H protons of tert-butyl
chain of Boc in all ILs 14–17 were observed in the region
of 1.29–1.40 ppm.−CH3 group attached via imidazole ring
displayed doublet peak for IL 14 at 3.85 ppm with coupling
constant J=7.0 Hz and singlet at 3.86 and 3.75 ppm for 15,
16, and 17.
In 1H NMR spectra of DPIL 14, two methylenic protons
(N–CH=CH=N) of imidazole ring appeared as multiplet
from δ=7.79 to 7.73 ppm while for DPILs 15, 16 methyl-
enic protons appeared as multiplet from 7.98 to 7.78 ppm
and in DPIL 17 two methylenic protons of imidazole ring
appeared as multiplet from 8.08 to 8.33 ppm, respectively.
The single proton (N=CH–N) in imidazole ring appeared as
1 3

S. A. Chaubey et al.
13C NMR signals in the range of δ = 48.1–48.7 ppm
displayed the formation of quaternary nitrogen in DPILs
14–17. The two carbons (− CH = CH −) of imidazole
ring in ILs appeared in the range of 123.2–123.3 ppm,
while third carbon as −N–C = N− appeared in the range
of 137.1–137.8 ppm. The two carbon peaks in DPILs
18–21 at 124 ppm and 117 ppm corresponding to the
anion [NTf2], while 19F peak for anion [NTf2] was found
at − 78.676, − 78.678, − 78.683, and − 78.675 ppm in
DMSO. ESI–MS positive mode spectra of the synthe-
sized DPILs 14–17 exhibited the molecular ion peaks at
m/z = 421.2852, 423.2817, 395.2613, and 471.3048, con-
frming their molecular masses.
(a)
T / °C
(b)
The water content of the DPILs viz. Boc-[Pro-Pro-
EMIM], Boc-[ Pro-Val-EMIM], Boc-[Pro-Ala-EMIM],
and Boc-[Pro-Phe-EMIM] measured by coulometric titra-
tion system were 0.02, 0.02, 0.04, and 0.02%, respectively.
The water content was constantly kept as low as possible
by continuously working under high vacuum environment
since the presence of water could lower the maximum sol-
ubility signifcantly.
The entire synthesized DPILs showed good solubility
in polar solvents like H2O, DMSO, CH3OH, C2H5OH, and
CH3CN. Thus the synthesized peptide-based ionic liquids
which eliminate the use of traditional solvent vehicles may
have immense potential for efective formulation of poorly
water-soluble drugs.
T / °C
Fig. 1 TGA (solid line) and DTG (dotted line) of synthesized ionic
liquid containing chloride and bis(trifuoromethyl)sulfonamide anions
Thermal properties of proline-based dipeptide imida-
zolium ionic liquids 14–21 were measured by TGA and
DSC are summarized in Table 1. The temperature-ramped
TGA experiments were performed in triplicate for each
ionic liquid in order to validate the reproducibility of the
Tonset measurement. TGA revealed a clear improvement in
thermal stability of the NTf2 (bis(trifuoromethane)sulfon-
imide) (Fig. 1b) as compared to the Cl (Fig. 1a) because
NTf2 anion formed stronger hydrogen bond due to the pres-
ence of highly electronegative fuorine atom. TGA results
obtained for the ionic liquid Boc-[Pro-Pro-EMIM][NTf2]
(18) showed the percent mass and the rate of mass loss
as a function of the temperature. The thermal degradation
of the compound was monitored as a large mass loss at
385 °C (48.71%) due to decomposition of anion in dipep-
tide linkage.
Figure 2 shows the DSC curves of diferent dipeptide-
based ionic liquids 14–17. Figure 2a revealed a Tg of −42,
− 36, − 34, and − 21 °C for chloride anion-based pep-
tide ionic liquids. A broad endothermic peak appeared at
95.30, 64.66, and 94.80 °C appears to be the melting point
of the corresponding ILs. Thus it proves the ionic liquid
characteristics of compounds 14, 15, 17. That Boc-[Pro-
Ala-EMIM][Cl] does not show any endothermic melting
peak which reveals an amorphous nature of the compound.
Table 1 Thermophysical
Thermal properties
Compounds
properties of synthesized
proline-based dipeptide
imidazolium ionic liquids
(DPILs) 14–21
14
15
16
17
18
19
20
21
T
decom/°Ca
200
95.30
−34
190
64.66
−42
175
ND
−21
195
94.80
−36
385
76
ND
300
102
ND
300
76.33
ND
390
72
ND
M.p. /°Cb
Tgonset/°Cc
ND not detected
aOnset of decomposition temperature monitoring by TGA (10 °C/min)
bMelting point
cGlass transition temperature
1 3

Synthesis of novel proline-based imidazolium ionic liquids
and Boc-[Pro-Phe-EMIM][Cl]/[NTf2] exhibited improved
thermal stabilities. The entire synthesized DPILs showed
good solubility in polar solvents. Furthermore, the good
yields, mild conditions, and suitable facile procedure con-
frmed that this method would play a vital role in synthesis
of more diverse peptide-based chiral ionic liquids. Currently,
we are investigating the efects of these peptide ionic liquids
in organocatalyst reactions and design of tandem processes.
(a)
T / °C
Experimental
T / °C
All the reagents were commercially available and were used
without further purifcation. All amino acids used were of
the l-series. Solvents were purifed according to the litera-
ture protocol and freshly distilled prior to use. 1H NMR and
13C NMR spectra were recorded on a Bruker NMR spec-
trometer at 400 MHz and 100 MHz, respectively. The Fou-
rier transform infrared (FT-IR) spectra of the DPILs were
recorded on a JASCO- 4700 FT-IR spectrophotometer in an
attenuated total refectance (ATR) mode. All spectra were
obtained with accumulation of 32 scans in the wave number
range of 4000–600 cm−1. Moisture content was analyzed
by Karl Fischer (Metrohm 860 KF coulometer) in solu-
tion combi columat fritles (500 cm3) coulometric titration
System. TGA was carried out using a thermogravimetric
analyzer (TA SDT Q600) in nitrogen at a heating rate of
10 °C min−1 from 25 to 600 °C. DSC was performed in a
METLER TOLEDO DSC1 from −50 to 100 °C for chloride
anion ionic liquids and −20 to 160 °C for NTf2 anion ionic
liquids in an N2 atmosphere.
(b)
T / °C
Fig. 2 DSC curve of synthesized ionic liquid containing chloride and
bis(trifuoromethyl)sulfonamide anions
The bis(trifuromethanesulfonyl)imide (NTf2) anion-based
peptide ionic liquids DSC was performed from − 20 to
110 °C. Figure 2b does not reveal any Tg in the measured
temperature zone which might appear by lowering the start-
ing temperature in DSC. Dipeptide ionic liquids Boc-[Pro-
Pro-EMIM][NTf2], Boc-[Pro-Ala-EMIM)][NTf2], and Boc-
[Pro-Phe-EMIM][NTf2] in Fig. 2b shows clear endothermic
melting peaks at 76, 76.33, and 72 °C.
Synthesis of dipeptide functionalized ILs
In a round bottom fask, 2.15 g Boc-Pro-OH (10 mmol)
was taken and dissolved in 20 cm3 anhydrous DCM. Then,
2.78 cm3 Et3N (20 mmol) was added to it followed by 1.14
cm3 ethyl chloroformate (12 mmol). The reaction mix-
ture was stirred at − 5 °C under nitrogen atmosphere for
30 min. The l-proline methyl ester hydrochloride (1.65 g,
10 mmol) was taken in another round bottom fask and dis-
solved in ~ 5 cm3 DMF at 0 °C. Et3N (1.52 cm3, 11 mmol)
was added to it and stirred at room temperature for 10 min.
The free amino acid methyl ester in DMF was directly
added to the freshly prepared mixed anhydride. Then, the
reaction mixture was stirred at − 5 °C for 30 min and was
brought to room temperature and stirred for 8–14 h. After
completion of the reaction (monitored by TLC), the reac-
tion mixture was diluted with 100 cm3 ethyl acetate, the
organic layer was extracted using 50 cm3 water, and the
organic phase was washed with 50 cm3 brine. The ethyl
acetate layer was dried over anhydrous sodium sulfate and
the solvent was removed under reduced pressure to aford
The results of DSC further prove and validate to be room
temperature ionic liquids. The relatively straightforward
synthetic procedure and the presence of chiral centers in
the precursors are a remarkable advantage in our approach.
Conclusions
We have synthesized a series of novel dipeptide ionic liq-
uids based on proline dipeptide and functionalized meth-
ylimidazolium having excellent yields and purity. The
synthesized compounds were visibly transparent viscous
liquids at room temperature. All the synthesized dipeptide
ionic liquids Boc-[Pro-Pro-EMIM][Cl]/[NTf2], Boc-[Pro-
Val-EMIM][Cl]/[NTf2], Boc-[Pro-Ala-EMIM][Cl]/[NTf2],
1 3

S. A. Chaubey et al.
Boc-Pro-Pro-OMe. The residue was then purifed using
column chromatography as reported in literature protocol
[37].
1‑(S)‑2‑[(S)‑1‑Carboxy‑2‑phenylethylcarbamoyl]pyrroli‑
dine‑1‑carboxylic acid tert‑butyl ester (Boc‑Pro‑Phe‑OH, 9,
C19H26N2O5) [38, 39] Yield: 74%; m.p.: 121 °C; column:
1
The dipeptide methyl ester (Boc-Pro-Pro-OMe) was
dissolved in methanol. Aqueous NaOH (2 M, 1.5 eq) was
then added dropwise. The reaction mixture was stirred at
room temperature for 4–6 h. The progress of the reaction
was measured by TLC. After completion of the reactions,
organic solvent was removed on a rotary evaporator and the
pH of the aqueous solution was adjusted to 2–3 with 1 N
HCl. The aqueous layer was washed twice with ethyl acetate.
The organic layer was dried with MgSO4and was concen-
trated to give desired crude product which was purifed by
silica gel (230–400 mesh) column chromatography eluting
with a solution of ethyl acetate/hexane.
EtOAc/hexane; TLC: Rf = 0.32 (EtOAc/hexane 6:4); H
NMR (400 MHz, CDCl3): δ=8.77 (br, s, 1H), 7.27–7.23 (m,
2H), 7.20–7.14 (m, 3H), 6.86 (br s, 1H), 4.86 (br s, 1H), 4.22
(br s, 1H), 3.35–3.24 (m, 2H), 3.06 (dd, 1H, J= 13.9 Hz,
5.6 Hz), 2.17 (m, 1H), 1.86 (m, 1H), 1.74 (br s, 2H), 1.39 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3): δ=174.0, 172.9,
155.3, 136.1, 129.3, 128.4, 127.0, 81.4, 80.7, 61.0, 60.0,
52.9, 46.9, 37.5, 30.8, 29.7, 28.2, 24.3, 23.3 ppm.
Synthesis of the Boc‑dipeptide‑2‑chloroethylamide
10
The dipeptides 7, 8, and 9 were prepared from the same
procedure as the preparation of compound 6.
To the suspension of 0.312 g dipeptide Boc (Pro-Pro)-OH
(6, 1 mmol) in 10 cm3 CH2Cl2, 0.278 cm3 Et3N (2 mmol)
was added at 10 °C. Then 0.286 cm3 ethyl chloroformate
(3 mmol) was added dropwise and stirred for 30 min at
0 °C. The 2-chloroethylamine hydrochloride salt (0.139 g,
1.2 mmol) was dissolved in 2–3 cm3 DMF at 0 °C. Et3N
(0.167 cm3, 11 mmol) was added to it and stirred at room
temperature for 30 min. The free 2- chloroethylamine in
DMF was directly added to freshly prepare mixed anhydride
of Boc (Pro-Pro)-OH and stirred for 8–14 h at room tem-
perature. Progress of reaction was monitored by TLC. The
mixture was diluted with 50 cm3 ethyl acetate and the solu-
tion was washed with water and saturated brine solution. The
organic layer was dried over Na2SO4 and concentrated on
rotary evaporator. The residue was purifed by fash column
chromatography on silica gel to give Boc-Pro-Pro-2-chlo-
roethylamide (10).
(S)‑1‑[(S)‑1‑(tert‑Butoxycarbonyl)pyrrolidine‑2‑car‑
bonyl]pyrrolidine‑2‑carboxylic acid (Boc‑Pro‑Pro‑OH, 6,
C15H24N2O5) Yield: 65%; m.p.: 91 °C; column: EtOAc/
1
hexane; TLC: Rf = 0.24 (EtOAc/hexane 6:4); H NMR
(400 MHz, CDCl3): δ=4.65–4.15 (m, 2H), 3.81–3.75 (m,
1H), 3.63–3.34 (m, 3H), 2.24–1.82 (m, 8H), 1.47–1.39 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3): δ=176.7, 175.8,
155.9, 154.7, 154, 81.0, 80.4, 59.4, 59.3 (rotamer), 58.9,
58.6 ( rotamer), 57.8, 57.6 (rotamer), 46.8, 46.7 (rotamer),
30.8, 30.0, 29.7, 29.4, 28.4, 28.3 (rotamer), 28.2, 28.1 (rota-
mer), 24.9, 24.2, 24.1,23.6 ppm.
(S)‑1‑[(S)‑2‑[(tert‑Butoxycarbonyl)amino]‑3‑methylbu‑
tanoyl]pyrrolidine‑2‑carboxylic acid (Boc‑Pro‑Val‑OH, 7,
C15H26N2O5) Yield: 78%; m.p.: 98 °C; column: EtOAc/
The compounds 11, 12, and 13 were prepared using the
same procedure as the preparation of compound 10.
1
hexane; TLC: Rf = 0.20 (EtOAc/hexane 6:4); H NMR
(400 MHz, CDCl3): δ=7.46 (br, s, 1H), 7.28 (br, s,1H), 7.01
(br, s, 1H), 4.49–4.41 (m, 1H), 4.25 (d, 1H, J = 13.9 Hz),
3.64–3.34 (m, 3H), 2.17–2.01 (m, 1H), 1.90–1.83 (m, 2H),
1.47–1.37 (m, 9H), 1.29–1.28 (m, 6H) ppm; 13C NMR
(100 MHz, CDCl3): δ=176.4, 175.3, 173.0, 172.4, 155.8,
155.1, 80.7, 61.3, 59.7, 57.1, 48.1, 47.0, 31.9, 28.3, 24.6,
23.7, 20.7, 19.1 ppm.
2‑[2‑(2‑Chloroethylcarbamoyl)pyrrolidine‑1‑carbonyl]pyrro‑
lidine‑1‑carboxylic acid tert‑butyl ester (Boc‑Pro‑Pro‑2‑chlo‑
roethylamide, 10, C17H28ClN3O4) Yield: 57%; m.p.: 81 °C;
column: EtOAc/hexane; TLC: Rf =0.60 (EtOAc/hexane 6:4);
1H NMR (400 MHz, CDCl3): δ=8.51 (br, s, 1H), 7.32 (br, s,
1H), 6.52 (br, s, 1H), 5.33(s, 1H), 4.84–3.38 (m, 8H), 1.89
(m, 4H), 1.47 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3):
δ=172.7, 80.9, 60.7, 59.9, 59.0, 47.0, 44.9, 43.7, 42.2, 41.2,
39.1, 31.1, 29.7, 28.5, 24.6, 23.8 ppm.
(S)‑2‑[(S)‑1‑Carboxyethylcarbamoyl]pyrrolidine‑1‑carboxylic
acid tert‑butyl ester (Boc‑Pro‑Ala‑OH, 8, C13H22N2O5) Yield:
69%; m.p.: 114 °C; column: EtOAc/hexane; TLC: Rf =0.36
(EtOAc/hexane); 1H NMR (400 MHz, CDCl3): δ=7.42 (br,
s,1H), 6.91 (br, s, 1H), 4.41 (dd, 1H, J=13.9 Hz, 5.6 Hz),
4.13 (dd, 1H, J=13.9 Hz, 5.6 Hz), 2.99 (dd, 1H, J=13.9 Hz,
5.6 Hz), 2.94 (dd, 1H, J=13.9 Hz, 5.6 Hz), 2.24–2.04 (m,
1H), 1.87 (br s, 2H), 1.60–1.24 (s, 9H) ppm; 13C NMR
(100 MHz, CDCl3): δ=175.3, 172.9, 155.3, 80.9, 61.0, 59.8,
48.1, 47.1, 31.1, 136.1, 129.3, 128.4, 127.0, 81.4, 80.7, 61.0,
60.0, 52.9, 46.9, 31.1, 28.3, 24.5, 23.7 ppm.
2‑[1‑(2‑Chloroethylcarbamoyl)‑2‑methylpropylcar‑
bamoyl]pyrrolidine‑1‑carboxylic acid tert‑butyl ester
(Boc‑Pro‑Val‑2‑chloroethylamide, 11, C17H30ClN3O4) Yield:
87%; m.p.: 113 °C; column: EtOAc/hexane; TLC: Rf =0.52
(EtOAc/hexane 6:4); 1H NMR (400 MHz, CDCl3): δ=7.23
(br, s, 1H), 7.02 (br, s, 1H), 6.28 (br, s, 1H), 4.33–4.22 (m,
3H), 3.59–3.42 (m, 8H), 2.36–1.85 (m, 8H), 1.47 (s, 9H),
0.96–0.89 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3):
1 3

Synthesis of novel proline-based imidazolium ionic liquids
δ=172.2, 80.8, 77.1, 60.8, 58.4, 47.3,43.2, 41.3, 31.3, 29.1,
1‑[2‑[2‑[(1‑tert‑Butoxycarbonylpyrrolidine‑2‑carbonyl]‑
amino)‑3‑methylbutyrylamino]ethyl]‑3‑methyl‑3H‑im‑
idazol‑1‑ium chloride (Boc‑(Pro‑Val‑EMIM)(Cl), 15,
C21H36ClN5O4) Yield: 74%; column: acetone (100%); TLC:
Rf =0.55 (EtOAc/methanol 50/50); FT-IR (ATR): ꢀ =3262,
2972, 2834, 2361, 1652, 1538, 1412, 1239, 1165, 1126,
1021, 920 cm−1; 1H NMR (400 MHz, DMSO-d6): δ=9.2–
9.12 (m, 1H, Im), 8.51–8.34 (m, 1H, Im), 7.98–7.78 (m, 1H,
Im), 7.60 (s, 1H, NH), 6.89 (s, 1H, NH), 4.31–4.22 (m, 3H,
CH2 and Val), 4.05–3.95 (m, 1H, Pro), 3.86 (s, 3H, NCH3),
3.58–3.28 (m, 4H), 2.13–2.09 (m, 1H, Val), 1.92–1.74 (m,
4H), 1.40–1.29 (m, 9H, Boc), 0.83–0.74 (m, 6H, Val) ppm;
13C NMR (100 MHz, DMSO-d6): δ=171.7, 153.6, 137.4,
128.1, 123.3, 122.6, 120.5, 78.6, 58.8, 48.4, 46.6, 35.7, 32.8,
30.9, 29.9, 29.3, 28.0, 23.9, 23.1, 21.1, 19.1, 18.3 ppm.
24.2, 19.4, 18.8, 17.0 ppm.
2‑[1‑(2‑Chloroethylcarbamoyl)ethylcarbamoyl]pyrroli‑
dine‑1‑carboxylic acid tert‑butyl ester (Boc‑Pro‑Ala‑2‑chlo‑
roethylamide, 12, C15H26ClN3O) Yield: 80%; m.p.: 69 °C;
column: EtOAc/hexane; TLC: Rf = 0.29 (EtOAc/hexane
6:4); 1H NMR (400 MHz, CDCl3): δ=7.46 (br, s, 1H), 7.21
(br, s, 1H), 7.01 (br, s, 1H), 6.83 (br, s, 1H), 4.49 (m, 1H),
3.64–3.34 (m, 6H), 2.17–1.83 (m, 5H), 1.45–1.37 (m, 9H)
ppm; 13C NMR (100 MHz, CDCl3): δ=172.5, 80.7, 77.1,
60.6, 49.0, 47.3, 42.9, 41.4, 31.0, 29.7, 29.3, 28.9, 28.5,
28.4, 24.6, 17.7 ppm.
2‑[1‑(2‑Chloroethylcarbamoyl)‑2‑phenylethylcarba‑
moyl]pyrrolidine‑1‑carboxylic acid tert‑butyl ester
(Boc‑Pro‑Phe‑2‑chloroethylamide, 13, C21H30ClN3O4) Yield:
85%; colorless liquid; column: EtOAc/hexane; TLC:
Rf =0.56 (EtOAc/hexane 6:4); 1H NMR (400 MHz, CDCl3):
δ = 8.53 (br, s, 1H), 7.98 (m, s, 1H), 7.31–7.07 (m, 9H),
6.73 (s, 1H), 6.52 (s, 1H), 4.89–4.05 (m, 6H), 3.54–3.06
(m, 13H), 2.28 (s, 1H), 1.43–137 (s, 9H) ppm; 13C NMR
(100 MHz, CDCl3): δ=172.8, 171.8, 170.9, 155.6, 136.4,
129.2, 128.6, 127.1, 80.7, 77.0, 60.9, 60.4, 59.7, 54.2, 53.2,
47.2, 42.5, 41.5, 38.9, 37.3, 29.5, 28.3, 24.4, 23.5, 21.0 ppm.
1‑[2‑[2‑[(1‑tert‑Butoxycarbonylpyrrolidine‑2‑carbonyl)‑
amino]propionylamino]ethyl]‑3‑methyl‑3H‑imidazol‑1‑ium
chloride (Boc‑(Pro‑Ala‑EMIM)(Cl), 16, C19H32ClN5O4) Yield:
60%; column: acetone (100%); TLC: Rf = 0.55 (EtOAc/
methanol 50/50); FT-IR (ATR): ꢀ = 3233, 2983, 2837,
2361, 1650, 1544, 1416, 1248, 1165, 1018 cm−1; 1H NMR
(400 MHz, DMSO-d6): δ = 9.18–9.07 (m, 1H, Im), 8.67–
8.34 (m, 1H, Im), 8.18–7.99 (m, 1H, Im), 7.78–7.71 (m, 2H),
7.64 (s, 1H, NH-Im), 7.13–7.12 (s, 1H, NH), 6.91 (s, 1H,
NH), 4.30–4.10 (m, 3H, Ala), 3.87–3.86 (m, 2H), 3.66 (s,
1H), 3.61–3.11 (br, s, water) 2.10–1.72 (m, 3H, Ala-CH3),
1.39–1.11 (m, 9H, Boc) ppm; 13C NMR (100 MHz, DMSO-
d6): δ=172.5, 153.7, 137.4, 127.9, 123.0, 120.5, 78.6, 59.3,
48.3, 46.6, 35.7, 32.9, 30.9, 29.8, 28.0, 24.0, 23.2, 18.1,
17.4 ppm.
Synthesis of the (Boc‑dipeptide ethyl
methylimidazolium) chloride (14)
To 0.372 g Boc-Pro-Pro-2-chloroethylamide (10, 1 mmol),
0.82 g N-methylimidazole (1.1 mmol) was added and the
mixture was stirred at 75 °C for~24 h. After completion of
the reaction, the solvent was removed by decantation and the
obtained viscous solution was purifed by column chroma-
tography on silica gel using acetone and methanol as eluent
to furnished yellowish color viscous liquid product 14.
The compounds 15, 16, and 17 were prepared from the
same procedure as the preparation of compound 14.
1‑[2‑[2‑[(1‑tert‑Butoxycarbonylpyrrolidine‑2‑carbonyl)‑
amino]‑3‑phenylpropionylamino]ethyl]‑3‑methyl‑3H‑im‑
idazol‑1‑ium chloride (Boc‑(Pro‑Phe‑EMIM)(Cl), 17,
C25H36ClN5O4) Yield: 74%; m.p.: 121 °C; column: EtOAc/
hexane 4:6); TLC: Rf =0.55 (EtOAc/methanol 50/50); FT-IR
(ATR): ꢀ =3255, 2950, 2837, 2360, 1651, 1557, 1414, 1243,
1165, 1018 cm−1; 1H NMR (400 MHz, DMSO-d6): δ=9.25-
9.08 (m, 1H, Im), 8.80–8.68 (m, 1H, Im), 8.33–8.08 (m, 1H,
Im), 8.23 (s, 1H, NH), 7.76–7.17 (m, 1H, Ar), 7.36 (s, 1H,
NH), 7.30–7.17 (m, 4H, Ar), 4.50–4.36 (m, 1H), 4.26- 3.92
(m, 4H, CH2), 3.75 (s, 3H, CH3, Im), 3.57–3.22 (m, 4H, Pro
& CH2), 3.04–2.80 (m, 2H, Ar-CH2), 2.09–1.58 (m, 4H,
Pro), 1.29–1.12 (d, 9H, Boc) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 172.0, 153.6, 138.0, 137.4, 129.1, 128.0,
126.2, 124.6, 123.3, 122.6, 121.6, 78.7, 59.3, 54.2, 48.5,
46.6, 35.7, 33.8, 30.8, 29.7, 27.9, 23.8, 22.9 ppm.
1‑[2‑[[1‑(1‑tert‑Butoxycarbonylpyrrolidine‑2‑carbonyl)pyrro‑
lidine‑2‑carbonyl]amino]ethyl]‑3‑methyl‑3H‑imidazol‑1‑ium
chloride (Boc‑(Pro‑Pro‑EMIM)(Cl), 14, C21H34ClN5O4) Yield:
70%; column: acetone (100%); TLC: Rf = 0.55 (EtOAc/
methanol 50/50); FT-IR (ATR): ꢀ = 3255, 2982, 2837,
2361, 1643, 1563, 1417, 1249, 1165, 1017 cm−1; 1H NMR
(400 MHz, DMSO-d6): δ = 9.23–8.95 (m, 1H, Im), 8.33–
8.16 (m, 1H, Im), 7.79–7.73 (m, 1H, Im), 7.69 (s, 1H, NH),
4.40–4.38 (m, 1H, Pro), 4.24–4.19 (m, 3H), 3.85 (d, 3H,
J=5.6 Hz, NCH3), 3.57–3.37 (m, 6H, Pro), 2.10–1.72 (m,
8H, Pro), 1.39–1.32 (m, 9H) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 172.2, 171.1, 153.2, 137.2, 122.9, 78.3,
59.6, 57.4, 48.2, 46.6, 35.6, 29.5, 29.3, 28.3, 27.8, 24.6,
23.7, 23.2 ppm.
Anion exchange procedure
The aqueous solution of Boc-(Pro-Pro-EMIM)(Cl)
(14, 0.5 mmol) was dissolved in methanol and added to
1 3

S. A. Chaubey et al.
bis(trifuoromethane)sulfonimide lithium salt (0.5 mmol)
in methanol. The reaction mixture was stirred at room tem-
perature for 2–3 h. The precipitates appeared in the reac-
tion mixture was fltered to get corresponding ionic salts of
Boc-(Pro-Pro-EMIM)(NTf2) (18). The desired pure products
were dried in vacuum for 24 h.
(m, 3H, Ala-CH3), 1.38–1.12 (m, 9H, Boc) ppm; 13C NMR
(100 MHz, DMSO-d6): δ = 172.5, 136.9, 123.3, 122.4,
117.8, 59.3, 48.4, 46.4, 35.6, 34.5, 28.1, 28.0 ppm; 19F NMR
(376 MHz, DMSO-d6): δ=−78.683 ppm.
1‑[2‑[2‑[(1‑tert‑Butoxycarbonylpyrrolidine‑2‑car‑
bonyl)amino]‑3‑phenylpropionylamino]ethyl]‑3‑me‑
thyl‑3H‑imidazol‑1‑ium bis(trifuoromethylsulfonyl)imide
(Boc‑(Pro‑Phe‑EMIM)(NTf2), 21, C27H36F6N6O8S2) Yield:
96%; FT-IR (ATR): ꢀ = 3748, 3318, 2944, 2832, 2511,
1996, 1767, 1692, 1451, 1415, 1198, 1117, 1021, 675, 616,
515 cm−1; 1H NMR (400 MHz, DMSO-d6): δ=8.96–8.92
(m, 1H, Im), 8.5 (s, 1H, Im), 8.30 (m, 1H, Im), 8.06–7.90
(m, 1H, NH), 7.66 (s, 1H, Ar), 7.48 (s, 1H), 7.38(s, 1H),
7.25–7.19 (m, 4H, Ar), 4.45 (br, 1H), 4.18–4.17 (br, 2H,
CH2), 4.03 (br, 1H, CH), 3.95–3.78 (m, 4H, CH2-Pro), 3.02–
2.76 (m, 2H, Ar-CH2), 2.09–1.90 (m, 1H, Pro), 1.65–1.61
(br, 2H), 1.38–1.15 (m, 9H, Boc) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 136.7, 129.0, 128.0, 126.3, 123.4, 122.4,
121.0, 40.2, 117.8, 59.3, 35.7, 34.5, 28.0 ppm; 19F NMR
(376 MHz, DMSO-d6): δ=−78.675 ppm.
The compounds Boc-(Pro-Val-EMIM)(NTf2) (19), Boc-
(Pro-Ala-EMIM)(NTf2) (20), and Boc-(Pro-Phe-EMIM)
(NTf2) (21) were prepared from the same procedure as the
preparation of compound Boc-(Pro-Pro-EMIM)(NTf2) (18).
All the fnal products were obtained in high yield and purity
levels.
1‑[2‑[[1‑(1‑tert‑Butoxycarbonylpyrrolidine‑2‑carbonyl)pyrro‑
lidine‑2‑carbonyl]amino]ethyl]‑3‑methyl‑3H‑imidazol‑1‑ium
bis(trifluoromethylsulfonyl)imide (Boc‑(Pro‑Pro‑EMIM)
(NTf2), 18, C23H34F6N6O8S2) Yield: 95%; FT-IR (ATR):
ꢀ =3334, 2945, 2908, 2832, 2163, 1987, 1678, 1451, 1417,
1352, 1197, 1134, 1020, 616, 571, 528, 509 cm−1; 1H NMR
(400 MHz, DMSO-d6): δ=8.93 (m, 1H, Im), 8.05–8.04 (m,
1H, Im), 7.69–7.76 (d, 2H, NH-Im), 4.39–4.36 (m, 1H, Pro),
4.20–4.15 (m, 4H), 3.83 (d, 3H, NCH3), 3.73 (s, 1H), 3.61–
3.43 (m, 4H, Pro), 2.49–1.66 (m, 10H, Pro), 1.39–1.32 (m,
9H) ppm; 13C NMR (100 MHz, DMSO-d6): δ=171.5,153.2,
137.1, 124.3, 122.7, 121.1, 117.9, 114.7, 78.5, 59.6, 57.6,
48.3, 46.5, 35.6, 29.2, 28.0, 24.6, 23.3 ppm; 19F NMR
(376 MHz, DMSO-d6): δ= −78.676 ppm.
Acknowledgements We gratefully acknowledge fnancial support
from the Department of Science and Technology-SERB New Delhi,
(SERB/F/8435/2015-16). The author also thanks RSIC CDRI, Luc-
know and IISc, Bangalore for the spectral analysis.
1‑[2‑[2‑[(1‑tert‑Butoxycarbonylpyrrolidine‑2‑carbonyl)‑
amino]‑3‑methylbutyrylamino]ethyl]‑3‑methyl‑3H‑im‑
idazol‑1‑ium bis(trifluoromethylsulfonyl)imide
(Boc‑(Pro‑Val‑EMIM)(NTf2), 19, C23H36F6N6O8S2) Yield:
97%; FT-IR (ATR): ꢀ = 3371, 2975, 1661, 1530, 1419,
1183, 1053, 743, 608, 506, 459 cm−1; 1H NMR (400 MHz,
DMSO-d6): δ=9.04–8.94 (m, 1H, Im), 8.28–8.10 (m, 1H,
Im), 7.92–7.68 (m, 3H, Im), 7.14 (s, 1H, NH), 6.94 (s, 1H,
NH), 4.21 (br, s, 2H, CH2 & Val), 3.98–3.91 (m, 1H, Pro),
3.83 (s, 2H, NCH3), 3.65 (s, 1H), 3.49–3.35 (br, d, 3H),
2.07–1.85 (m, 3H, Val), 1.38–1.27 (m, 9H), 0.78–0.77 (m,
6H, Val) ppm; 13C NMR (100 MHz, DMSO-d6): δ=171.4,
137.2, 127.4, 123.0, 120.9, 117.8, 59.2, 57.9, 48.3, 46.5,
35.6, 33.0, 29.8, 28.0, 19.0, 17.7 ppm; 19F NMR (376 MHz,
DMSO-d6): δ=−78.678 ppm.
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