A potential greener protocol for peptide coupling reactions using recyclable/reusable ionic liquid [ C 4-DABCO ] [ N(CN) 2 ]

Article abstract of DOI:10.1007/s12039-018-1461-0

Abstract : Development of greener methodologies in synthetic organic chemistry has brought awareness in recent decades due to the ecological performance of green solvent media and catalytic systems. Here, we carried out the peptide bond formation reaction in one of the environmentally secure solvents, ‘ionic liquids’ in the presence of coupling reagent and in the absence of external base at room temperature, affording dipeptides in good to excellent yields. GRAPHICAL ABSTRACT: SYNOPSIS We carried out the peptide bond formation reaction in ionic liquids in the presence of a coupling reagent at room temperature, in the absence of an external base, affording dipeptides in good to excellent yields.

Full text of DOI:10.1007/s12039-018-1461-0

J. Chem. Sci. (2018) 130:53
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-018-1461-0
REGULAR ARTICLE
A potential greener protocol for peptide coupling reactions using
recyclable/reusable ionic liquid [C4-DABCO][N(CN)2]
MANASHJYOTI KONWARa, NAGESHWAR D KHUPSEb, PRAKASH J SAIKIAc and
DIGANTA SARMAa,∗
aDepartment of Chemistry, Dibrugarh University, Dibrugarh, Assam 786 004, India
bCentre for Materials for Electronics Technology, Pashan Road, Pune, Maharashtra 411 008, India
cAnalytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat, Assam 785 006,
India
E-mail: dsarma22@dibru.ac.in
MS received 6 November 2017; revised 28 March 2018; accepted 8 April 2018
Abstract. Development of greener methodologies in synthetic organic chemistry has brought awareness in
recent decades due to the ecological performance of green solvent media and catalytic systems. Here, we carried
out the peptide bond formation reaction in one of the environmentally secure solvents, ‘ionic liquids’ in the
presence of coupling reagent and in the absence of external base at room temperature, affording dipeptides in
good to excellent yields.
Keywords. Base free; green chemistry; ionic liquid; peptides synthesis.
1. Introduction
a vital role in practically all biological processes.8,9 Lit-
erature survey showed that in both solution and solid
phase, the C-terminal modified peptide fragments (pro-
tected and/or activated) can be readily stitched together
in segment condensations for the assembly of large pep-
tides or small proteins.10,11
The elementary reaction to synthesize the dipeptide
is the coupling of two amino acids. This reaction pro-
ceeds in homogeneous conditions in the presence of a
base such as NEt3, K2CO3, NaHCO3, etc., and a cou-
pling agent such as DCC, EDC, etc., along with some
promoters which increase the reaction rate.12
Literature survey reveals the use of imidazole-based
or incorporated ionic liquids for the synthesis of pep-
tides at room temperature or at elevated temperatures.
Galy et al.,13a recently reported the ionic liquid-assisted
peptide synthesis at room temperature, but the reac-
tion time for peptide coupling was quite long (24
h). Kühl et al.,13b reported peptide ligation reaction
showing different side chain reactions using 1-ethyl-
3-methylimidazolium acetate as an ionic liquid. Petiot
et al.,13c synthesized hydrophilic poly(ethylene glycol)-
ionic liquid medium for the peptide synthesis and
Seitkalieva et al.,13d reported peptide extraction through
ionic liquid of imidazolium-type.
The peptide synthesis has drawn significant importance
duetothemostresourcefulcarbon-nitrogenbondforma-
tion with the advantages like milder reaction conditions,
atom efficiency, tolerability to various functional groups
as well as its varied applications in a number of pharma-
ceutical, agrochemical and other industries.1,2 Peptide
synthesis deals with the amide bond formation of
amino acids in protein chemistry and encourages the
researchers for advanced synthesis in a smarter manner
like as nature does in living systems.3 Mimicking the
natural protocol for the peptide synthesis, the develop-
ment of speedy and proficient synthesis protocols has
been a feature in the pharmaceutical prospective of pep-
tides to be realized and would likely be welcomed.4–6
There were 55 peptide-based drugs developed and a
further 200 in clinical phases up to 2016. Many more
research works are going on which signify the pharma-
ceutical importance of peptide chemistry (Figure 1).7
The amide linkage is the universal feature in small
synthetic or natural molecules and proteins which play
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-018-1461-0) contains
supplementary material, which is available to authorized users.

53 Page 2 of 8
J. Chem. Sci. (2018) 130:53
NH
NH
ionic conductivity and afford superior solubility for an
extensive range of compounds (both organic and inor-
ganic).28–30 Ionic liquids can be considered as promising
and novel alternatives for organic solvents in synthetic
organic chemistry due to easy preparation and recycla-
bility, and their properties can be tuned by varying the
alkyl group and anion.31,32 Therefore, the main objective
of our work was to synthesize the dipeptide moieties in
greener and cheaper reaction conditions. In search of
greener methodologies, we mainly focused on the use
of ionic liquids that were liquid at room temperature
and basic in nature. Use of basic ionic liquid nullifies
the requirement of organic solvent and external base for
peptide coupling.
OH
OH
O
O
B
O
H
N
HN
OH
OH
NH
O
HN
O
HO
OH
OH
OH
O
Cl
O
NH
O
NH
O
HO
O
O
HN
HO
HO
O
HO
O
O
O
OH
O
O
O
Cl
NH
N
HN
A
OH
O
OH
O
O
H
N
N
H
O
O
O
H
H
NH2
N
N
N
N
N
HO
O
H
H
NH
O
O
HN
HN
N
O
NH
NH
NH
NH2
HN
O
O
C
NH
O
2. Experimental
Figure 1. Some biologically active peptide molecules. [A]
Bentiromide (exocrine pancreatic insufficiency screening);
[B] Dalbavancin (antibiotic); [C] Goserelin (anticancer).
All reagents and solvents were purchased from Sigma Aldrich
and Alfa Aesar and used without further purification unless
otherwise stated. All reported yields are isolated yields.
Peptide coupling reactions were performed on oven-dried
glassware at open air. 1H and 13C NMR spectra were recorded
on 400 and 100 MHz spectrometers at room temperature,
respectively. Chemical shifts are reported in parts per million
Similarly, Vallette et al.,14a and Chan et al.,14b−c car-
ried out peptide synthesis by the use of neutral ionic
liquids. But these methods have some shortcomings
such as the use of the external base, elevated reaction
temperature, low reaction yield, adverse effect on envi-
ronment leading to pollution.15,16 The role of coupling
agent in peptide bond formation is proved to be unfavor-
able when the coupling reaction is carried out in aqueous
condition.17 Base catalyzes the hydrolysis of amino acid
ester, which is used as a coupling partner, thus inhibit-
ing the reaction progress.18,19 It is, therefore, of prime
importance to build up recyclable and reusable homo-
geneous reaction conditions, which will formulate the
reaction more atom-economic.
It is becoming progressively more essential to replace
environmentally harmful volatile organic solvents in the
chemical manufacturing processes. Amongst the var-
ious alternative solvents such as water, polyethylene
glycol and supercritical fluids, a potential alternative is
the room-temperature ionic liquids (RTILs) to carry out
the organic reactions.20,21 Since these liquids are salts of
different cations and anions, we can design them sim-
ply by changing the cation or anion, known as “Designer
Solvents” in recent decades.22,23 The impressive effects
of ionic liquids on any reaction are due to the interaction
of cations and anions with solutes molecules and hence
they are of prime interest in the scholarly research and
industrial sectors.24–27 The much lower melting points of
room temperature ionic liquids compared to inorganic
salts can be partially attributed to the bulky cationic
groups. Theseliquidshavealowervapourpressure, non-
(ppm, ). Column chromatography was performed on silica
δ
gel (200–300 mesh). Thin layer chromatography (TLC) was
carried out using aluminium sheets pre-coated with silica gel
60F254 (Merck) and was visualized under 254 nm UV light.
2.1 Procedures
2.1a Preparationof[C4-DABCO][N(CN)2]: Inaround
bottom flask, a mixture of DABCO (5 g; 44.57 mmol) and n-
butyl bromide (6.10 g; 44.57 mmol) in 30 mL ethyl acetate
was added and stirred at room temperature, overnight. After
overnight stirring, neutral ionic liquid [C4-DABCO][Br] was
obtained as white solid. The reaction mixture was washed
with ethyl acetate four times for complete removal of n-butyl
bromide and other organic compounds. It was then subjected
to vacuum to obtain the pure solid [C4-DABCO][Br]. On the
other hand, silver dicyanamide (AgN[CN]2) was prepared
by mixing the equimolar amount of silver nitrate (7.33 g,
43.13 mmol) and sodium dicyanamide (3.84 g, 43.13 mmol)
in water. Freshly prepared silver dicyanamide was added to
the [C4-DABCO][Br] in water and stirred overnight at room
temperature. Water was removed in vacuum to obtain the pure
[C4-DABCO][N(CN)2] as a colourless liquid. Yield = 98%.
2.1b Preparation of [EMIM][BF4]: In a round bottom
flask, a mixture of 1-methyl imidazole (4.1 g; 50 mmol) and
ethyl bromide (5.45 g, 50 mmol) was stirred at 80 ◦C in neat
condition for 10 h. After that, neutral ionic liquid [EMIM][Br]
was obtained as white solid. The reaction mixture was washed
with ethyl acetate four times for complete removal of n-ethyl
flammable, high chemical and thermal stability, superior bromide and other organic compounds. It was then subjected

J. Chem. Sci. (2018) 130:53
Page 3 of 8 53
to vacuum to obtain the pure solid [EMIM][Br]. After that, mmol) was added to the [OMIM][Br] in acetone and stirred
sodium tetrafluoroborate (5.3 g, 48.17 mmol) was added to overnight at room temperature to obtain [OMIM][OH]. The
the [EMIM][Br] in acetone and stirred overnight at room solution was filtered and acetone was removed in vacuum to
temperature to obtain [EMIM][BF4]. The solution was fil- obtain the pure [OMIM][OH] as dark brown liquid.
tered and acetone was removed in vacuum to obtain the pure
[EMIM][BF4] as a colorless liquid.
2.1g Preparation of [BMIM][N(CN)2]: In a round
bottom flask, a mixture of 1-methyl imidazole (4 g; 48.78
mmol) and n-butyl bromide (6.7 g; 48.78 mmol) was stirred
at 80 ◦C in neat condition for 10 h. After that, neutral ionic
liquid [BMIM][Br] was obtained as white solid. The reac-
tion mixture was washed with ethyl acetate four times for
complete removal of n-butyl bromide and other organic com-
pounds. It was then subjected to vacuum to obtain the pure
solid [BMIM][Br]. On the other hand, silver dicyanamide
(AgN[CN]2) was prepared by mixing equimolar amount of
silver nitrate (7.72 g, 45.66 mmol) and sodium dicyanamide
(4.07 g, 45.66 mmol) in water. Freshly prepared silver
dicyanamide was added to the [BMIM][Br] in acetone and
stirred overnight at room temperature. The solution was fil-
tered and acetone was removed in vacuum to obtain the pure
[BMIM][N(CN)2] as colourless liquid.
2.1c Preparation of [EMIM][OH]: In a round bot-
tom flask, a mixture of 1-methyl imidazole (4.1 g; 50 mmol)
and ethyl bromide (5.45 g, 50 mmol) was stirred at 80 ◦C
in neat condition for 10 h. After that, neutral ionic liquid
[EMIM][Br] was obtained as white solid. The reaction mix-
ture was washed with ethyl acetate four times for complete
removal of n-ethyl bromide and other organic compounds.
It was then subjected to vacuum to obtain the pure solid
[EMIM][Br]. After that, potassium hydroxide (2.7 g, 48.15
mmol) was added to [EMIM][Br] to get [EMIM][OH]. The
solution was filtered and acetone was removed in vacuum
to obtain the pure [EMIM][BF4] as a colorless liquid and
[EMIM][OH] as a brown liquid.
All the ionic liquids are reported in the literature and were
synthesized and characterized following the existing proce-
dures.33
2.1d Preparation of [BMIM][BF4]: In a round bot-
tom flask, a mixture of 1-methyl imidazole (4 g; 48.78 mmol)
and n-butyl bromide (6.7 g; 48.78 mmol) was stirred at 80 ◦C
in neat condition for 10 h. After that, neutral ionic liquid
[BMIM][Br] was obtained as white solid. The reaction mix-
ture was washed with ethyl acetate four times for complete
removal of n-butyl bromide and other organic compounds.
It was then subjected to vacuum to obtain the pure solid
[BMIM][Br]. After that, sodium tetrafluoroborate (5 g, 45.66
mmol) was added to the [BMIM][Br] in acetone and stirred
overnight at room temperature to obtain [BMIM][BF4]. The
solution was filtered and and acetone was removed in vacuum
to obtain the pure [BMIM][BF4] as colorless liquid.
2.2 General reaction procedure for peptide synthesis
In a 50 mL round bottom flask, a mixture of N-benzoyl
glycine (1 mmol, 0.179 g), glycine methyl ester hydrochlo-
ride (1.5 mmol, 0.188 g), EDC.HCl (1 equiv.) in [C4-
DABCO][N(CN)2] (3 mL) was added and stirred at room
temperature for 4 h. After completion of the reaction (by TLC
monitoring), the reaction mixture was extracted with diethyl
ether (3 × 10 mL) and the organic layer was washed with
distilled water (20 mL), dried over anhydrous Na2SO4 and
the organic layer was evaporated in vacuum. The residue was
purified by column chromatography on silica gel using ethyl
acetate/hexanes (1:1) as eluent to get the corresponding pep-
tide.
2.1e Preparation of [BMIM][OH]: In a round bottom
flask, a mixture of 1-methyl imidazole (4 g; 48.78 mmol)
and n-butyl bromide (6.7 g; 48.78 mmol) was stirred at 80 ◦C
in neat condition for 10 h. After that, neutral ionic liquid
[BMIM][Br] was obtained as white solid. The reaction mix-
ture was washed with ethyl acetate four times for complete
removal of n-butyl bromide and other organic compounds.
It was then subjected to vacuum to obtain the pure solid
[BMIM][Br]. After that, potassium hydroxide (2.5 g, 44.75
mmol) was added to [BMIM][Br] to get [BMIM][OH]. The
solution was filtered and and acetone was removed in vacuum
to obtain the pure [BMIM][OH] as dark brown liquid.
3. Results and Discussion
In continuation of our work on peptide synthesis and
applications of room temperature ionic liquids,34,35 we
have designed and synthesized a series of ionic liquids
based on imidazole and DABCO and demonstrated their
applications on peptide synthesis (Figure 2). One of the
most important agents in peptide synthesis is the cou-
pling reagent which is necessary to couple the amine
and acid group of two amino acid residues in pres-
ence of a base.36,37 The mostly used coupling reagents
in peptide synthesis are DCC, EDC.HCl, DIC, etc.
Ionic liquids based on imidazolium cations are likely
to be unstable under basic condition.38 Superior acidity
2.1f Preparation of [OMIM][OH]: In a round bottom
flask, a mixture of 1-methyl imidazole (4 g; 48.78 mmol) and
n-octyl bromide (9.42 g; 48.78 mmol) was stirred at 80 ◦C
in neat condition for 10 h. After that, neutral ionic liquid
[OMIM][Br] was obtained as white solid. The reaction mix-
ture was washed with ethyl acetate four times for complete
removal of n-octyl bromide and other organic compounds.
It was then subjected to vacuum to obtain the pure solid
[OMIM][Br]. After that, potassium hydroxide (2.65 g, 47.25 at C-2 position of imidazole results in deprotonation

53 Page 4 of 8
J. Chem. Sci. (2018) 130:53
N
1-2). The same reaction in four basic ionic liquids
[EMIM][OH], [BMIM][OH], [C4-DABCO][N(CN)2]
and [OMIM][OH] afforded dipeptides in 40%, 65%,
98% and 78%, respectively (Table 1; entries 3–6).
The same reaction in basic ionic liquid [C4-DABCO]
[N(CN)2] in the absence of coupling agent did not
afford any dipeptide indicating the necessity of a cou-
pling agent (Table 1; entry 7). From this outcome,
[C4-DABCO][N(CN)2] was found to be the most excel-
lent and suited basic ionic liquid for peptide synthesis
at room temperature. The efficiency of the DABCO-
based ionic liquids in peptide synthesis, as compared to
other ionic liquids, is due to the presence of two nitrogen
atoms at the bicyclo ring of DABCO and dicyanamide
anion has high value of conductivities.41 High viscos-
ity of the ionic liquid is a detrimental factor for their
use as an alternative solvent in organic synthesis. The
ionic liquids based on dicyanamide anion, however,
exhibit much lower viscosity than ionic liquids with
other anions and these ionic liquids are considered as
effective solvents for organic reactions due to the high
complexing capability of dicyanamide anion.42 To the
bestofourknowledge, nosuchobservationsarereported
so far for carrying out peptide synthesis in basic ionic
liquid.
N
N
+
-
+
-
N
-
[BF4]
N
[N(CN)2]
[BF4]
N
C4H9
[EMIM][BF4]
[BMIM][BF4]
[C4-DABCO][N(CN)2]
(
)
N
7
N
N
+
+
+
-
-
-
N
[OH]
[OH]
N
N
[OH]
[EMIM][OH]
[BMIM][OH]
[OMIM][OH]
N
N(CN)2
N
[BMIM][N(CN)2]
Figure 2. Ionic liquids used in this study.
1.C6H5COCl in NaOH
O
H
O
2.Conc. HCl, 00
C
Ph
N
H2
N
OH
OH
O
New C-N bond
forms
Glycine
Bz-Glycine
O
Coupling agent
H
N
COOMe
Ph
N
H
O
Ionic liquids
RT
Bz-Gly-Gly methyl ester
O
1.CH3OH, SOCl2, 00
C
H2
N
O
OH
H2
N
OMe. HCl
2.
Δ
Glycine
Glycine methyl
ester hydrochloride
Amino acids with different electron rich substituent
were used to construct the dipeptide moiety in the
absence of an external base and organic media-free envi-
ronment (Table 2). Under this reaction condition, each
amino acid with various electron rich groups reacts
Scheme 1. General reaction conditions for synthesis of
dipeptide.
leading to the formation of N-heterocyclic carbenes to afford the dipeptide in reasonably higher yields.
which may lead to complexation and/or breakdown The coupling of Bz-glycine and glycine methyl ester
side reactions.39 From this point, the ionic liquid/base hydrochloride afforded Bz-Gly-Gly-methyl ester with a
combination could be detrimental for carrying out promising yield of 80% in 4 h (Table 2, entry 1). How-
organic transformation. Therefore, our concern was to ever, there are some amino acids giving poor yields of
develop a base and organic media-free green protocol dipeptides which may due to the presence of more bulky
for the peptide synthesis. In our work, peptide syn- phenyl rings (Table 2, entries 5,6,11-15). Good to excel-
thesis was carried out in basic ionic liquids in the lent results of peptide coupling were obtained for amino
absence of any external base. We carried out peptide acids with less bulky substituent (Table 2, entries 2-4,7-
synthesis in five different basic ionic liquids; namely, 10) under this reaction condition.
i) 1-butyl-1,4-diazabicyclo[2.2.2]octane dicyanamide,
In order to show the useful application of the solvent
[C4-DABCO][N(CN)2], ii) 1-butyl-3-methylimidazo- system consisting of ionic liquids and EDC.HCl, it is
lium hydroxide, [BMIM][OH], iii) 1-ethyl-3-methylim- very important to recycle and reuse the catalytic system.
idazoliumhydroxide, [EMIM][OH], iv)1-octyl-3-meth- It was seen that the catalytic system could be recovered
ylimidazolium hydroxide [OMIM][OH], and v) 1-butyl- and reused up to four times without any significant loss
3-methylimidazolium dicyanamide [BMIM][N(CN)2] in its activity (Table 3).
(Figure 2).40 Peptide synthesis was also carried out in
To perform the recyclability test, in a 50 mL round
neutral ionic liquids [EMIM][BF4] and [BMIM][BF4] bottom flask, a mixture of N-Bz glycine (1 mmol,
but in the presence of an external base. 0.179 g), glycine methylester hydrochloride (1.5 mmol,
The reaction of N-benzoyl glycine and glycine methyl 0.188 g), EDC.HCl (1 mmol, 0.192 g) in [C4-DABCO]
ester hydrochloride in presence of EDC.HCl in neu- [N(CN)2] (3 mL) were added and stirred at room temper-
tral ionic liquids [EMIM][BF4] and [BMIM][BF4] did ature for 4 h (Table 3, entry 1). After completion of the
not proceed at all even after 12 h (Table 1, entries reaction (by TLC monitoring), the resulting mixture was

J. Chem. Sci. (2018) 130:53
Page 5 of 8 53
Table 1. Optimization of the base and the solvent system for the peptide
synthesis.a
O
O
Ionic liqiud, RT
Coupling agent
H
N
O
H
Ph
N
H
C
O
N
H
COOMe.HCl
+
COOMe
Ph
N
H
H
O
Bz-glycine
Glycine methyl
Bz-Gly-Gly methyl ester
ester Hydrochloride
Entry
Solvent (IL)
Coupling agent Time (h) Yieldb(%)
1
2
3
4
5
6
[EMIM][BF4]
[BMIM][BF4]
[EMIM][OH]
[BMIM][OH]
EDC.HCl
EDC.HCl
EDC.HCl
EDC.HCl
EDC.HCl
EDC.HCl
12
12
4
4
4
4
12
12
n.r.
n.r.
40
65
98
78
[C4-DABCO][N(CN)2]
[OMIM][OH]
7
8
[C4-DABCO][N(CN) ]
–
n.r.
50
[BMIM][N(CN)2] 2
EDC.HCl
aReaction conditions: benzoyl glycine (1 mmol), glycine methyl ester
hydrochloride (1.5 mmol), EDC.HCl (1 mmol), ionic liquid (3 mL) at room
temperature.
bisolated yield.
Table 2. Effect of substituent on peptide synthesis.a
Table 3. Recyclability test of the peptide synthesis.a
O
R1
R2
O
O
[C4-DABCO][N(CN)2
EDC.HCl, RT, 4 hrs
]
R1
H
N
H
N
O
[C4-DABCO][N(CN)2
]
O
H
H
O
H
H
Ph
N
H
C
O
N
H
COOMe.HCl
+
Ph
N
H
C
O
N
H
COOMe.HCl
+
COOMe
R2
COOMe
Ph
N
H
EDC.HCl, RT, 4 hrs
Ph
N
H
O
O
amino acid
methyl ester
hydrochloride
benzoyl protected
amino acid
Glycine methyl
Dipeptides
Bz-glycine
ester Hydrochloride
Bz-Gly-Gly methyl ester
Entry
R1
R2
-H
-CH3
-CH3
-H
-H
-CH3
-H
-CH3
-H
-CH3
-CH2-Ph
-CH2-Ph
-CH2-Ph
-CH2-Ph
-CH2-Ph
Yieldb(%)
1
2
3
4
5
6
7
8
-H
-CH3
-H
98
85
81
83
76
75
79
77
75
79
76
74
70
72
71
-CH3
-CH2-Ph
-CH2-Ph
−CH(CH )2
−CH(CH3)2
3
9
-CH2-CH(CH )2
10
11
12
13
14
15
-CH2-CH(CH3)2
3
aReaction conditions: benzoyl glycine (1 mmol), glycine
methyl ester hydrochloride (1.5 mmol), EDC.HCl (1 mmol),
[C4-DABCO][N(CN)2] (3 mL) at room temperature.
bisolated yield.
-H
-CH3
-CH2-Ph
-CH(CH3)2
-CH2-CH(CH3)2
ctime 5 h.
aReactionconditions:benzoylprotectedaminoacid(1mmol),
amino acid methyl ester hydrochloride (1.5 mmol), EDC.HCl
(1 mmol), [C4-DABCO][N(CN)2] (3 mL) at room tempera-
ture. bisolated yield.
the ionic liquid [C4-DABCO][N(CN)2] was prepared in
water and hence it is completely miscible with water.
4. Conclusions
extracted with diethyl ether (3 × 10 mL) and the ether
layerwasseparatedandthecatalyticmediumwasreused This communication has summarized the development
for next four runs (Table 3, entries 2-5). Any attempt of a highly efficient ionic liquid-mediated peptide syn-
to wash the catalytic medium by water was avoided as thesis protocol. It is comprehensible that the ionic

53 Page 6 of 8
J. Chem. Sci. (2018) 130:53
liquids are similar in function with many other solvents
in solution phase strategy.43 Peptide coupling reactions
were successfully carried out in an ‘organic solvent and
external base’ free condition, affording peptides in good
to excellent yields at room temperature. Due to the dual
function, “alternative green solvent and base” of basic
ionic liquids, it is believed that their use in organic trans-
formation, peptidesynthesisinparticular, willgainmore
attention in near future.
7. (a) Sachdeva S 2016 Peptides as ‘drugs’: the journey
so far Int. J. Pept. Res. Ther. 1 https://doi.org/10.1007/
s10989-016-9534-8; (b) Meneses C, Nicoll S L and
Trembleau L 2010 Multigram-scale synthesis of short
peptides via a simplified repetitive solution-phase pro-
cedure J. Org. Chem. 75 564; (c) Albericio F 2004
Developments in peptide and amide synthesis Curr.
Opin. Chem. Biol. 8 211; (d) Aravinda S, Shamala N,
Roy R S and Balaram P 2003 Non-protein amino acids in
peptide design Proc. Indian Acad. Sci. (Chem. Sci.) 115
373; (e) Islam M N, Islam M S, Hoque M A, Kato T and
Nishino N 2015 Synthetic strategy for bicyclic tetrapep-
tides HDAC inhibitors using ring closing metathesis J.
Chem. Sci. 127 1563
Supplementary Information (SI)
8. Montalbetti C A G N and Falque V 2005 Amide bond
formation and peptide coupling Tetrahedron 61 10827
9. Toplak A, Nuijens T, Quaedflieg P J L M, Wu B and
Janssen D B 2015 Peptide synthesis in neat organic sol-
vents with novel thermostable proteases Enzyme Microb.
Technol. 74 20
General experimental procedure, NMR & MS spectra for all
compounds with full characterization data are available as
Supplementary Information at www.ias.ac.in/chemsci.
Acknowledgements
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M.K. is thankful to UGC for UGC-BSR fellowship. D.S. is
thankful to DST, New Delhi, India for a research Grant [No.
EMR/2016/002345]. The authors acknowledge the Depart-
ment of Science and Technology for financial assistance
under DST-FIST programme and UGC, New Delhi for Spe-
cial Assistance Programme (UGC-SAP) to the Department of
Chemistry, Dibrugarh University.
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