N, N -Dimethylpyridin-4-amine (DMAP) based ionic liquids: Evaluation of physical properties via molecular dynamics simulations and application as a catalyst for Fisher indole and 1 H -tetrazole synthesis

Article abstract of DOI:10.1039/c7ra06824g

The last few decades have seen a rapid increase in the use of ionic liquids (ILs) as a green alternative to traditional solvents in organic synthesis. The use of ILs as catalysts has also increased in recent years. Herein we the report synthesis of new N,N-dimethylpyridin-4-amine (DMAP) based ionic liquids (ILs) as new and efficient catalysts for the facile synthesis of indoles (via Fischer indole synthesis), and 1H-tetrazoles (via click chemistry). The method is environmentally friendly, requiring only minimum catalyst loading (0.2 equiv. for Fischer indole synthesis). In the case of 1H-tetrazole formation (via click chemistry), the reaction was carried out under a solvent free environment. Moreover, thermal studies (TGA, DTG and DSC) of DMAP-ILs (2, 3) have also been carried out to elicit their stability for temperature dependent reactions. Application of molecular dynamics simulations provided valuable insights into the structural and transport properties of these ionic liquids. An MP2 method was applied to evaluate the stability of the compound via binding energy calculations.

Full text of DOI:10.1039/c7ra06824g

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PAPER
N,N-Dimethylpyridin-4-amine (DMAP) based ionic
liquids: evaluation of physical properties via
molecular dynamics simulations and application as
a catalyst for Fisher indole and 1H-tetrazole
synthesis†
Cite this: RSC Adv., 2017, 7, 34197
b
Sarfaraz Ali Ghumro,‡a Sana Saleem,‡a Mariya al-Rashida,
Nafees Iqbal,a
c
a
a
a
*
*
Rima D. Alharthy, Shakil Ahmed, Syed Tarique Moin and Abdul Hameed
The last few decades have seen a rapid increase in the use of ionic liquids (ILs) as a green alternative to
traditional solvents in organic synthesis. The use of ILs as catalysts has also increased in recent years.
Herein we the report synthesis of new N,N-dimethylpyridin-4-amine (DMAP) based ionic liquids (ILs) as
new and efficient catalysts for the facile synthesis of indoles (via Fischer indole synthesis), and 1H-tetrazoles
(via click chemistry). The method is environmentally friendly, requiring only minimum catalyst loading (0.2
equiv. for Fischer indole synthesis). In the case of 1H-tetrazole formation (via click chemistry), the reaction
was carried out under a solvent free environment. Moreover, thermal studies (TGA, DTG and DSC) of
DMAP-ILs (2, 3) have also been carried out to elicit their stability for temperature dependent reactions.
Application of molecular dynamics simulations provided valuable insights into the structural and transport
properties of these ionic liquids. An MP2 method was applied to evaluate the stability of the compound via
binding energy calculations.
Received 19th June 2017
Accepted 29th June 2017
DOI: 10.1039/c7ra06824g
rsc.li/rsc-advances
the design and applications of ILs.7 The use of ILs as catalyst for
organic syntheses has increased in the recent past. The ideal
1. Introduction
properties of ILs, such as low volatility, high thermal stability,
and ease of re-cyclization further adds to their appeal.2,8 Nitrogen
containing cationic scaffolds, typically pyridine or imidazole,
with various counter ions have been widely employed for cata-
lyzing different organic reactions.9 However, imidazole's inert
nature10 and extreme toxicity, and volatility of pyridine impedes
their utilization in organic syntheses and urges the discovery and
development of new ionic liquids with less toxic cations. N,N-
Dimethylpyridin-4-amine (DMAP), is a pyridine based non-
volatile, crystalline reagent. It has been extensively used as
a catalyst in organic syntheses, especially in coupling reactions,
such as esterication, amide formation and for protecting func-
tional groups (i.e. TBS, Boc) (Fig. 1).11,12
Although the concept of ionic liquids (ILs) has been around for
more than a hundred years, a sudden surge in the interest of
applications of ILs in both academia and industry has only been
witnessed in the last three decades or so.1–5 Traditionally, ILs
were dened as salts being made up of positively and negatively
charged ions that are liquid at temperatures typically below
100 ꢀC.2 However strict adherence to this criteria of an IL being
liquid at temperature below 100 ꢀC is no longer valid, and many
high temperature ILs are also known.6 ILs are widely regarded
as “designer liquids”, where, according to the particular appli-
cation, individual cationic or anionic moieties can be inde-
pendently selected allowing us to tailor the physiochemical
properties of ILs as desired, thereby introducing exibility in
In the present study, we have synthesized new DMAP-based
ionic liquids via N-alkylation, and successfully employed them
as catalyst for Fisher indole/indolenine and 1H-tetrazole
formation. To the best of our knowledge, DMAP-based ionic
liquids have neither been synthesized nor employed as catalyst
to mediate organic reactions. The commercially available DMAP
was treated with alkyl bromide to get the corresponding N-
alkylated cations with bromide anions. Owing to the docu-
mented nature of uoride ions as catalyst and as a mild base in
various organic reactions,13 the afore mentioned N-alkylated
cations with bromide ions were subjected to anion exchange
aH. E. J. Research Institute of Chemistry, International Center for Chemical and
Biological Sciences, University of Karachi, Karachi-75270, Pakistan. E-mail: tarique.
syed@iccs.edu; abdul.hameed@iccs.edu; Fax: +92-21-3481901; Tel: +92-21-
99261774; +92-21-99261701-2
bDepartment of Chemistry, Forman Christian College,
A Chartered University,
Ferozepur Road-54600, Lahore, Pakistan
cDepartment of Chemistry, Science and Arts College, Rabigh Campus, King Abdulaziz
University, Jeddah, Saudi Arabia
† Electronic supplementary information (ESI) available: NMR spectra of the
synthesized compounds. See DOI: 10.1039/c7ra06824g
‡ Shared rst author (contributed equally).
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Fig. 1 Structures of imidazolium, pyridinium, TBAF and N,N-dime-
thylamino pyridinium fluoride.
Scheme 1 Synthesis of DMAP-based ionic fluoride salts. Reaction
conditions: (a) pentyl or heptyl bromides, toluene, heated at reflux
(118–120 ꢀC); (b) treatment with silver fluoride aqueous solution.
with uoride ions. The resulting DMAP-IL (dimethylamino
pyridinium with uoride counter anion) could effectively serve
as a substitute for tetra butyl ammonium uoride (TBAF),
a well-known catalyst and IL that has been used to promote
different chemical reactions (Scheme 1).13–15 The DMAP-based
ionic liquids (2, 3) with uoride counter anions were then
investigated for their efficiency as catalysts for synthesis of tet-
rahydro-1H-carbazole (indoles)/methyl tetrahydro-1H-carbazole
(indolenines) (Fig. 2a) and 1H-tetrazole (Fig. 2b) compounds.
Indole is a bicyclic hetero-aromatic scaffold which serves as
an important structural component in many medicinally
important compounds such as serotonin, melatonin, alosetron
etc.16 For the synthesis of this important scaffold, a number of
synthetic protocols have been reported, however, Fisher indole
synthesis remains one of the most popular and signicant
methods. A typical method involves coupling of a ketone with
arylhydrazine to from an arylhydrazone, with subsequent
release of ammonia via [3,3]-sigmatropic arrangement under
acidic conditions to furnish the indole ring. Since the devel-
opment of indol formation by Fisher, a range of different
catalysts such as protic acids (H2SO4, polyphosphoric acid, HCl,
AcOH), Lewis acids (TiCl4, ZnCl2, PCl3), and imidazole17 or
pyridine18 based ionic liquids, have been used to catalyze indole
synthesis. Recently low melting mixtures, also called deep
Fig. 2 (a) Structures of different substituted tetrahydro-1H-carbazole
(indoles)/methyl tetrahydro-1H-carbazole (indolenines). Note: all the
reactions have been carried out by using DMAP-IL (2) catalyst (0.2
equiv.) in ethanol. (b) DMAP-IL catalyzed synthesis of substituted
1H-tetrazoles (8a–f).
eutectic solvents (DES), have also been used to carry out indole
formation.19 In these reactions, the low melting mixture (DES)
was used in large quantity, i.e. up to a gram in one mmol scale
reaction, adding dreariness to its removal from the reaction
mixture. In the present study, we prepared new DMAP-based
ionic liquids (Scheme 1) and successfully employed them as
catalysts with minimum loading in indole formation (Table 1,
Fig. 2a). In addition, DMAP-ILs has also be used to perform click
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Table 1 Optimization of Fisher indole synthesis using DMAP-ILs
properties vary signicantly when subtle changes are made in
the structure of cation and anion pairs.32 Other properties such
as viscosity and conductance depends on the diffusivity of ions
i.e. viscosity becomes low and conductance gets higher, as the
diffusion of ions is fast, therefore, the estimation of diffusion of
ions would be helpful for the designing of new ionic liquids.33
Both structural and transport properties were extensively
studied via molecular dynamics (MD) simulations.34,35 The
simulation methods were successfully applied to obtain reliable
information related to both structure and transport properties
of ionic liquids. Self-diffusion properties were recently reported
for newly synthesized quinolone based ionic uoride salts
(QuFs) using molecular dynamics simulations.36 A similar
procedure was adopted to evaluate structure and transport
properties of DMAP based ionic liquids in bulk. Self-diffusion
coefficients and viscosities of these ionic liquids were also
computed. The stability of ionic liquids is of prime importance,
therefore, binding energies were computed for the DMAP ionic
liquids using the second order Møller–Plesset (MP2) perturba-
tion theory method.
Entry
DMAP-ILs
Equivalenta
% yield (6a)
1
2
3
4
5
2
2
2
3
3
0.05
0.2
0.3
0.05
0.2
68
89
91
48
64
a
Catalytic amount of DMAP-ILs in ethanol.
reaction for 1H-tetrazole synthesis under solvent-free
conditions.
Tetrazole is a nitrogen containing, ve membered ring which
serves as an isosteric substituent of carboxylic acid. It serves as
important structural component in several molecules of phar-
maceutical interest.20 The presence of 1H-tetrazole species in
drug molecules has been known to favorably enhance their
metabolic resistance and pharmacokinetic properties.21 Tetra-
zoles have been found signicant importance in coordination
chemistry, as well as they have also shown great importance in
a large number of synthetic transformations as intermedi-
ates.22–24 Being an analog and metabolically stable substitute of
a carboxyl group, the tetrazole ring is extensively used in
molecular design and in the synthesis of modied amino acids
and peptidomimetics.22,25 This area of chemistry has strong
impact since the last two decades emphasizing on the popular
synthesis and applications of tetrazoles.26,27
The term click chemistry was introduced by Sharpless et al. by
preforming [2 + 3] cycloaddition between nitrile and azide
moieties to form the tetrazole.28 The tetrazole formation reaction
was usually catalyzed by using zinc metal,29–31 however, Amantini
et al. developed metal free conditions for click reaction. They
used tetrabutyl ammonium uoride (TABF) as catalyst for tetra-
zole formation by reacting nitrile species with trimethylsilyl
azide.15 In the context of developing metal free click reaction of
tetrazole formation, we synthesized new N,N-dimethylamino
pyridinium cation with uoride anion as alternate of TBAF in
1H-tetrazole synthesis due to their easy handling and rapid
preparation from commercially available solid 4-dimethylami-
nopyridine. The new DMAP-based ionic liquids were successfully
employed them as catalysts with minimum loading (0.2 equiva-
lent) tetrazole formation. Moreover, the removal of DMAP-based
ionic liquids from the reaction mixture was also found easy. The
catalytic efficiency of DMAP-IL (2) in click chemistry of 1H-tet-
razole formation was explored by reacting different benzonitriles
with azide source, i.e. trimethylsilyl azide, under solvent-free
conditions (Fig. 2b).
2. Results and discussion
2.1. Chemistry
A general scheme for the preparation of DMAP-based ionic
liquids (DMAP-ILs) comprises of two steps i.e. (a) N-Alkylation of
dimethylamino pyridine (DMAP), and (b) exchange of bromide
counter anion with uoride anion. The yields of nal DMAP-ILs
(2, 3) with uoride counter anion were found to be 78% and
75%, respectively (Scheme 1). The newly synthesized DMAP-ILs
were then employed as catalyst in organic synthesis; (1) Fisher
indole synthesis and (2) 1H-tetrazole formation. The catalyst
(2, 3) can be easily removed via simple aqueous work-up from
the reaction mixture.
A typical reaction of Fisher indole synthesis, between phenyl
hydrazine and cyclohexanone, was carried out by using DMAP-
based ionic liquids as catalyst, in ethanol as a solvent, affording
the desired product 7 in excellent yield. The reaction conditions
were optimized by varying the amount of DMAP-IL catalysts
(2, 3) as shown in Table 1. The percentage yield (89%) of
corresponding indole (2,3,4,9-tetrahydro-1H-carbazole) up on
addition of 0.2 equiv. of DMAP based IL (2), was found to be
comparable to the yield (91%) obtained while using 0.3 equiv. of
DMAP-IL. Accordingly, DMAP-based ionic liquid (2) as catalyst
Ionic liquids have a wide range of applications in different
disciplines including energy and biological sciences and the
evaluation of physical properties of ionic liquids such as
viscosity, melting point, boiling point etc. must be known prior
to their applications. To evaluate these properties for the related
applications a rational approach based on systematic methods
is needed to design efficient ionic liquids consisting of appro-
priate ionic pairs. Among such properties, the transport
Scheme 2 Fisher indole synthesis using DMAP-IL as catalyst (2).
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with 0.2 equiv. was opted for further investigating the scope of
DMAP-based catalyst (Scheme 2).
By utilizing the optimized conditions, a range of different
substituted phenyl hydrazine hydrochlorides were treated with
cyclohexanone or 2-methyl cyclohexanone to furnish the cor-
responding tetrahydro-1H-carbazole (indoles)/methyl tetrahy-
dro-1H-carbazole (indolenines) derivatives (6a–h) in variable
yields (Fig. 2a). No indole formation was observed in case of 2,4-
dinitrophenyl hydrazine even on increasing the temperature
ꢀ
(up to 100 C) and reaction time to 14 h. It may be due to the
electron withdrawing effects of nitro groups which hampered
the requisite cyclization of phenyl ring with cyclohexane to
complete the corresponding indole scaffold. However, the
reaction occurred smoothly with phenyl hydrazine, 40-methoxy
and 40-uorophenyl hydrazine to afford indoles 6a (89%), 6b
(78%) and 6c (75%) in good yields. The slight low yield (75%) of
60-uoro substituted indole 6c may be due to electron with-
drawing effect of uoro substituent. The reaction of 2-methyl
cyclohexanone with methoxyphenyl hydrazine in the presence
of catalyst (2) yielded corresponding indole (6d) in modest
yields (56%). While the reaction of 2-methyl cyclohexanone with
20-chloro substituted phenyl hydrazine gave corresponding
80-chloro indolenine (6e) in 76% and with 30-bromo substituted
phenyl hydrazine afforded 70-bromo indolenine (6g) as a major
regioisomeric product in 55% yield. The reaction of 40-cyano
substituted phenyl hydrazine with cyclohexanone produce cor-
responding indole (6f) in moderate yield (60%) due to strong
electron withdrawing effect of cyano group yield. The reaction of
1,3-cyclohexanediones (dimedone) with phenylhydrazine, gave
low yield (17%) of corresponding indole (6h) due to the
formation of stable N-phenylhydrazone intermediate which is
difficult to activate for the next [3,3] sigmatropic rearrangement
to furnish the corresponding indole (6h) (Fig. 2a).
Further, the click reaction of 1H-tetrazole formation between
benzonitrile and trimethylsilyl azide (TMSN3) was carried out in
the presence of DMAP-IL (0.3 equiv.) as a catalyst. The reaction
occurred smoothly and gave the desired 1H-tetrazole in good to
moderate yield (78–48%). TMSN3 was used as an azide source.
Because of uoride anion's greater affinity for silyl group, there
is a much more efficient release of active azide for click reaction
of tetrazole formation.15,37 To further broaden the scope of
DMAP-based ionic uoride liquid (2) as a catalyst, click reac-
tions with different substituted benzonitriles and TMSN3 were
carried out. In all cases, the 1H-phenyl tetrazoles (8a–f) were
obtained in good yields. The yield of unsubstituted phenyl tet-
razole (8a, 48%) was found low in comparison to methyl
substituted phenyl tetrazole (8b, 78%). This could be due to
electron donating effect of methyl group which enhanced the
reactivity of cyano group. The yields of halogen substituted (Cl,
Br, F) phenyl tetrazoles (8c, 59%), (8d, 68%), and (8f, 58%) were
found less compared to (8b). This is due to electron with-
drawing effect of halogen substituents. Further among halogen
substituted phenyl tetrazoles, the percentage yield with more
electronegative substituents F and Cl was found to be less as
compared to least electronegative substituents Br. The yield of
methoxy substituent bearing phenyl tetrazole (8e) was also
found to be good (70%). The structures of synthesized
Fig. 3 DMAP-IL 2, (a) overlap of TGA (blue) and DTG (purple) graphs;
(b) overlap of TGA (blue) and DSC (green) graphs: DMAP-IL 3, (c)
overlap of TGA (blue) and DTG (purple) graphs; (d) overlap of TGA
(blue) and DSC (green) graphs.
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compounds 8a–f were conrmed with NMR spectroscopy and
mass spectrometry (Fig. 2b).
2.2. Thermal studies
Thermal studies of DMAP-ILs (2, 3) were also conducted to
signify the efficiency of catalyst in temperature dependent
reactions. Thermal stability and decomposition pattern was
evaluated by carrying out thermogravimetric analysis (TGA),
derivative thermogravimetry (DTG), and differential scanning
calorimetry (DSC) (Fig. 3). Fig. 3a shows overlap of thermogra-
vimetric (TGA) graph and its rst derivative (DTG) for
compound (2), and Fig. 3b shows overlap of TGA and DSC
graphs. In the rst step, there is a gradual loss of weight (16%),
in the temperature range from ambient to 70 ꢀC, this is probably
due to the loss of water molecules. Immediately aer this step,
the onset of degradation is observed in the temperature range
70 ꢀC to 140 ꢀC where weight loss of 16% is observed, from DTG
Fig. 5 Radial distribution functions between center of masses of
cation and anion in both DMAP ionic liquids.
ꢀ
the rst decomposition temperature appears at 135 C. In the
third and nal step remaining weight loss (60%) is observed in
based ionic liquids, such as density, structural and transport
properties which could further help in expanding the application
of DMAP-based ionic liquids. Similarly, the newly synthesized
DMAP based ionic liquids demonstrated their signicances as
catalysts, yet further applications of these ionic liquids would
depend on the bulk properties which were evaluated via molec-
ular dynamics simulations. Fig. 4 illustrates variation of densities
of DMAP-ILs (2) and (3) at room temperature as a function of
time. Average densities of 1.00 ꢁ 0.02 and 0.99 ꢁ 0.02 g cmꢂ3
were obtained for DMAP-ILs (2) and (3) at room temperature,
thus showing no effect of the alkyl chain lengthening in the two
ionic liquids.
The structural attributes of DMAP ILs (2) and (3) were
primarily analyzed via radial distribution functions (RDFs)
plotted between center of mass of cations and anions i.e. pyr-
idinium and uoride ions. Fig. 5 depicts the RDF proles of
cation–anion interaction in both cases, minimal distances of
the range 140 ꢀC to 310 ꢀC, the decomposition temperature for
ꢀ
this step is observed at 265 C. All three weight loss steps are
accompanied by an endothermic change as can be seen from
the DSC data (Fig. 3). Similarly, the thermal analysis (TGA, DTG
and DSC) of compound 3 data has been obtained. Conse-
quently, Fig. 3c shows overlap of thermogravimetric (TGA)
graph and its rst derivative (DTG) and Fig. 3d shows overlap of
TGA and DSC graphs. As the compound is heated from ambient
temperature to 140 ꢀC a weight loss of 32% is observed, this is
most likely due to the loss of water. Aer this step, the
decomposition is observed in the temperature range from
200 ꢀC to 340 ꢀC, during which the remaining weight loss (52%)
is observed. The decomposition temperature calculated from
DTG is 260 ꢀC. This step is accompanied by an endothermic
change as can be seen from the DSC data (Fig. 3d).
˚
2.35 A were deduced from the rst peak of both RDFs. The RDF
2.3. Theoretical studies of DMAP-IL (2, 3)
patterns were very much similar to that of quinoline based ionic
liquids previously investigated by us,36 thus demonstrating that
the size and structural features of the cation had no signicant
inuence on the cation–anion interaction. The rst peaks were
continued to well-structured second and third shell peaks at
2.3.1. Bulk properties. Molecular dynamics simulations
were carried out to investigate the bulk properties of DMAP
˚
3.32 and 4.26 A along with few more peaks showing a long range
inuence of cations on anion or vice versa. A very sharp rst
peak was attributed to the strong electrostatic attraction
between cations and their respective anions whereas second
and third peak with low density corresponded to electrostatic
interaction between cations and anions of opposite ion pairs.
To further resolve the characteristic differences between the
two DMAP ionic liquids i.e. compounds 2 and 3, RDFs were
plotted between atomic pairs of cations and anions as shown in
Fig. 6. The distribution function between nitrogen atoms of
pyridinium ion and uoride ions (gC–A) in DMAP ILs (2) and (3)
exhibited identical well-dened rst peaks with maxima at 3.75
˚
A, which demonstrates the strong attraction between cations
and anions based on electrostatics forces. A difference in the
gC–A prole of the two ionic liquids was observed, and that
Fig. 4 Densities of DMAP (2) and (3) ionic liquids as a function of
simulation time.
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Fig. 7 Radius of gyration in DMAP based ionic liquids.
gyration obtained from MD simulation of DMAP ILs (2) and (3).
The Rg distribution plot yielded the most probable values of 20.6
˚
and 21.6 A for DMAP (2) and (3), respectively. In both plots,
˚
shoulder peaks were visible at 20.8 and 21.9 A showing the
exibility of alkyl side chain of different length. This further
encouraged us to evaluate the transport properties of both ionic
Fig. 6 (a) Radial distribution functions between N atoms of pyridinium
ions (C–C), between fluoride ions (A–A) and between the N atoms of
pyridinium ions and fluoride ion (C–A) of the DMAP (2) ionic liquids; (b)
radial distribution functions between N atoms of pyridinium ions (C–
C), between fluoride ions (A–A) and between the N atoms of pyr-
idinium ions and fluoride ion (C–A) of the DMAP (3) ionic liquids.
difference was a bit higher intensity of the rst peak in case of
DMAP (3), as compared to its corresponding DMAP derivative.
˚
The gC–A prole yielded a tiny shoulder peak at ꢃ4.35 A along
with the rst peak which was attributed to the electron delo-
calization of the dimethyl amine attached to pyridinium ring
that undergoes isomerization to produce dimethyl ammonium
ion – a typical isomer of DMAP which may interact with uoride
ions and is involved in a number of catalytic reactions. More-
over, a similar trend was observed in the distribution functions
of both ionic liquids between nitrogen atoms of pyridinium
ions (gC–C) and uoride (gA–A) ions – no peak was observed in the
gC–C prole indicating no structure ordering of the pyridinium
ions which may be due to strong repulsion between cations
˚
whereas rst peak appeared at 5.96 A in case of gA–A prole of
uoride ions.
Both ionic liquids presented identical structural properties
evaluated via radial distribution functions, nevertheless it was
signicant to assess the effect of alkyl chain length that was
made possible by the evaluation of radius of gyration (Rg) of the
two ionic liquids. Fig. 7 depicts the distribution of the radius of
Fig. 8 Mean-square displacement (MSDs) of the pyridinium and
fluoride ions in the (a) DMAP (2) and (b) DMAP (3) ionic liquids; black
and gray lines are for the cation and anion, respectively.
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liquids, since transport properties were reported to be depen- initio calculations was in excellent agreement with the ther-
dent on the alkyl side chain attached to core structure of mogravimetric analysis for DMAP ILs (2) and (3) which yielded
different scaffolds.
respective optimal decomposition temperatures of 265 and
Fig. 8 illustrates the mean square displacement (MSD) of the 260 ꢀC thus showing identical stability of these compounds. The
pyridinium and uoride ions in the DMAP ILs (2) and (3), as correlation between structural properties and thermodynamics
obtained from MD simulations. The inuence of alkyl chains of properties in terms of radial distribution functions and binding
different length on the transport properties of DMAP based energies of DMAP based ionic liquids was observed, since both
ionic liquids were demonstrated via MSD analysis that the structural and thermodynamics properties of the two ionic
produced asymptotic plots similar to those observed in case of liquids were very close yet differences in the self-diffusion
quinolinium based ionic liquids. The transport properties of coefficients for cations and anions indicated the inuence of
cations with two different alkyl chains were reported to affect side chain dynamics on the transport properties. The inuence
the properties of anions, therefore, a somewhat similar of the side chain on the diffusion coefficients were correlated to
behavior was presumed for DMAP based ionic liquids. The MSD gyration radius which clearly shows the difference in the side
plots for the two ionic liquids presented a contrasting behavior, chain dynamics affecting the diffusion of cations and anions.
since the mean square displacement of both ions in the DMAP Self-diffusion coefficients were reported to be linearly varied
(2) was higher, indicating the fast motion of the alkyl side chain with the alkyl chain lengths38 but anomalies could be expected.
(cf. Fig. 8a). For the DMAP (3), the alkyl side chain did not follow
the same trend, since low chain motion was deduced from the
MSD plot shown in Fig. 8b. This could be due to strong elec-
3. Conclusion
trostatic interactions between cations and anions thus resulting In conclusion, two new ionic liquids (2, 3), based on N,N-
in ionic packing and restricting the fast motion of the alkyl dimethylpyridin-4-amine (DMAP) as head group have been
chain. From the MSD plot, self-diffusion coefficients (D) were synthesized and successfully employed as catalysts for the
computed using the Einstein relation.
preparation of indole/indolenine via Fischer indole synthesis,
and 1H-phenyl tetrazoles via click chemistry. The wide scope of
use of newly synthesized DMAP-ILs as efficient catalyst was
established by synthesizing series of different indoles (7–14),
and tetrazoles (17–22) in good yields (up to 89%). The reduced
toxicity of DMAP, as compared to pyridine offers advantages in
preparation of DMAP-IL and handling in organic reactions. Low
catalyst loading (0.2 equiv.) further adds to advantages in terms
of its facile removal from the reaction mixture during the
purication process. In addition, thermal stability of DMAP
based catalysts 2 and 3 has been demonstrated via TGA, DTG
and DSC studies. The rst successful application of new DMAP-
ILs in Fisher indole and 1H-tetrazole synthesis signies their
importance in organic syntheses. MD simulation provided
detailed insights into the anomalous behavior of the transport
properties of similar DMAP based ionic liquids. Large negative
values of binding energies demonstrated the stability of these
compounds which were corroborated with decomposition
temperature obtained from thermogravimetric analysis.
ꢀ
ꢁ
MSD
2nD ¼ lim
t/N
t
where n denotes the number of dimensions and it is equal to 3
in these cases whereas D represents diffusion coefficient.
Applying tting procedure to the MSD plots with asymptotic
linear region up to 2 ns corresponding to diffusion properties
for pyridinium and uoride ions, self-diffusion coefficients (D)
were computed from the MSD slopes overs 0–2 ns. The coeffi-
cient values for pyridinium and uoride ions in DMAP (2) were
computed as 1.92 ꢁ 0.01 ꢄ 10ꢂ6 and 6.09 ꢁ 0.14 ꢄ 10ꢂ6 cm2 sꢂ1
,
respectively. In case of DMAP IL (3), comparatively low values of
self-diffusion coefficients were obtained (0.92 ꢁ 0.06 ꢄ 10ꢂ6
and 0.38 ꢁ 0.03 ꢄ 10ꢂ6 cm2 sꢂ1 for pyridinium and uoride
ions, respectively). The coefficient value of the uoride ion in
DMAP IL (3) was lower in comparison to that of DMAP IL (2),
correlating with the corresponding RDF data (gC–A), attributing
the strong electrostatic interaction between cations and anions,
thus affecting the mobility of the uoride ions.
2.3.2. Stability of DMAP ILs (2) and (3). Thermal stability of
ionic liquids directs their applications in a number of industrial
processes, therefore the evaluation of thermal stabilities of
DMAP based ionic liquids was carried out in terms of binding
energies. The energy data was obtained by the application of
MP2 method on the HF optimized structures of DMAP ILs (2)
and (3). A very close value of binding energies was obtained as
listed in Table 2. Binding energy data obtained from the ab
4. Material and methods
N,N-Dimethylpyridin-4-amine (DMAP) ($99.0%), pentyl
bromide, heptyl bromide, toluene ($99.5%), potassium uo-
ride ($99.0%) were purchased from Sigma Aldrich and used
without any purication unless otherwise stated. Thin layer
chromatography (TLC) was carried out using silica gel 60
aluminium-backed plates 0.063–0.200 mm. Analytical grade
solvents such as ethyl acetate (EtOAc), diethyl ether, hexane and
methanol etc. were used. Short wavelength UV radiation at
254 nm was used for visualization of TLC plates. Staining
mixture such as basic potassium permanganate or vanillin were
also used for visualization of TLC plates. Infrared (IR) spectra
Table 2 Binding energies of DMAP based ionic liquids obtained from
MP2 calculations
DMAP-ILs
2
3
1
Energy (kcal molꢂ1
)
131.3
131.2
were recorded on Bruker Vector-22 spectrometer. The H NMR
spectra were recorded on Bruker spectrometers at 300 MHz, 400
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MHz, 500 MHz, and 600 MHz, while 13C NMR spectra were 221.1 (M+ ꢂ Fꢂ), 220, 219; EI-HRMS (M+ ꢂ Fꢂ) C14H25N2 found
recorded at 75 MHz, 100 MHz, 125 MHz, 150 MHz in deuterated 221.1999, calculated 221.2018.
solvents. The chemical shis were recorded on the d-scale
(ppm) using residual solvents as an internal standard (DMSO;
1H 2.50, 13C 39.43 and CHCl3; 1H 7.26, 13C 77.16). Coupling
4.3. Procedure for substituted tetrahydro-1H-carbazole
(indoles)/methyl tetrahydro-1H-carbazole (indolenines)
synthesis
constants were calculated in hertz (Hz) and multiplicities were
labelled s (singlet), d (doublet), t (triplet), q (quartet), quint
(quintet) and the prexes br (broad) or app (apparent) were In a general procedure, an oven dried round bottomed ask
used. Mass spectra (EI+ and FAB) were recorded on Finnigan was charged with corresponding phenyl hydrazine hydro-
MAT-321A, Germany. Melting points of solids were determined chloride (1 mmol, 1 equiv.) and ethanol (3 mL). To the
using a Stuart™ melting point SMP3 apparatus.
resulting solution corresponding cyclohexanone/methyl
cyclohexanone (1 mmol, 1 equiv.) and 4-(dimethylamino)-1-
pentylpyridin-1-ium uoride (2) (0.2 mmol, 0.2 equiv.) was
added at room temperature and mixture was heated at reux
4.1. General synthetic procedure for DMAP-based ionic
uoride salts (2, 3)
ꢀ
(78–80 C) under nitrogen atmosphere. The consumption of
An over dried round bottomed ask was cooled to room starting material was monitored by thin layered chromatog-
temperature and charged with N,N-dimethylpyridin-4-amine raphy by using eluents ethyl acetate/hexane (3 : 7). The crude
(500 mg, 4.09 mmol, 1 equiv.), toluene (5 mL), and corre- reaction mixture was directly puried by silica gel column
sponding alkyl bromide (1 equiv.) at room temperature. The chromatography by using eluents in gradient eluents EtOAc/
reaction mixture was heated at reux (118–120 ꢀC) for 2 to 12 h hexane (1 : 9 to 1 : 1) to get the corresponding pure products
until no starting material was observed on TLC analysis. On (6a–h) in different yields.
cooling the resulting ionic salts, as oily solid which aer some
4.3.1. 2,3,4,9-Tetrahydro-1H-carbazole (6a). Yield 89% 1H
time became thick oil, was separated and washed further with NMR (400 MHz, DMSO-d6): dH 10.58 (1H, s, NH), 7.30 (1H, d, J ¼
cooled toluene and dried in vacuo. The obtained crude ionic 7.6 Hz, ArH), 7.20 (1H, d, J ¼ 8 Hz, ArH), 6.96 (1H, t, J ¼ 7.2 Hz,
liquids were treated with aqueous solution of silver uoride (4–5 ArH), 6.89 (1H, t, J ¼ 7.6 Hz, ArH), 2.68 (2H, t, J ¼ 5.6 Hz, CH2),
mL, 1 equiv.). Aerward, the precipitates of silver bromide were 2.60 (2H, t, J ¼ 5.4 Hz, CH2), 1.82–1.79 (4H, m, (CH2)2); MS-EI m/
removed by ltration and then water was evaporated with freeze z 171.1 (M+). The data is identical to those previously reported.39
drying process. The resulting residue was dissolved in chloro-
4.3.2. 6-Methoxy-2,3,4,9-tetrahydro-1H-carbazole
(6b).39
form, ltered and evaporated on rotary evaporator. The ob- Yield 78% 1H NMR (400 MHz, DMSO): dH 10.39 (1H, s, NH), 7.10
tained materials were occasionally washed with cooled toluene (1H, d, J ¼ 8.8 Hz, ArH), 6.81 (1H, d, J ¼ 2.0 Hz, ArH), 6.59 (1H,
or hexane to get the nal desired products DMAP-ILs (2 and 3). dd, J ¼ 8.4, 2.4 Hz, ArH), 3.71 (1H, s, OCH3), 2.63 (2H, t, J ¼
The obtained DMAP-ILs 2 and 3 were fully characterized with 5.6 Hz, CH2), 2.60 (2H, t, J ¼ 5.6 Hz, CH2), 1.79–1.77 (4H, m,
1H, 13C-NMR, IR, UV spectroscopy and mass spectrometry.
(CH2)2); MS-EI m/z 201 (M+).
4.3.3. 6-Fluoro-2,3,4,9-tetrahydro-1H-carbazole
(6c).40,41
Yield 74% 1H NMR (300 MHz, DMSO-d6): dH 10.69 (1H, s, NH),
7.19 (1H, dd, J ¼ 8.4, 3.8 Hz, ArH), 7.04 (1H, dd, J ¼ 10.0, 2.4 Hz,
4.2. Spectral data of DMAP-based ionic uoride salts
4.2.1. 4-(Dimethylamino)-1-pentylpyridin-1-ium uoride ArH), 6.76 (1H, td, J ¼ 9.6, 2.7 Hz, ArH), 2.67 (2H, t, J ¼ 5.4 Hz,
(2). Light yellow oil, (165 mg, 78%). 1H NMR (400 MHz, DMSO- CH2), 2.56 (2H, t, J ¼ 5.4 Hz, CH2), 1.82–1.75 (4H, m, CH2–CH2).
d6): dH 8.28 (2H, d, J ¼ 7.6 Hz, ArH), 7.02 (2H, d, J ¼ 7.6 Hz, ArH), MS-EI m/z 189.1 (M+).
4.14 (2H, t, J ¼ 7.2 Hz, CH2), 3.17 (6H, s, C(CH3)2), 1.75 (2H,
4.3.4. 6-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-carbazole
quint, J ¼ 7.4 Hz, CH2), 1.28 (2H, app quint, J ¼ 7.4 Hz, CH2), (6d). Yield 56% 1H NMR (400 MHz, DMSO-d6): dH 11.55 (1H, s,
1.18 (2H, app quint, J ¼ 7.4 Hz, CH2), 0.85 (3H, t, 7.2 Hz, CH3); NH), 7.33 (1H, d, J ¼ 8.4 Hz, ArH), 6.99 (1H, d, J ¼ 2.4 Hz, ArH),
13C NMR (100 MHz, DMSO-d6): dC 155.8 (C), 141.9 (CH ꢄ2), 6.86 (1H, dd, J ¼ 8.4, 2.4 Hz, ArH), 3.76 (3H, s, OCH3), 2.86–2.82
107.6 (CH ꢄ2), 56.6 (CH2), 39.7 (CH3 ꢄ2), 29.9 (CH2), 27.5 (1H, m, CH), 2.08 (1H, m, CHH), 1.81–1.78 (1H, m, CHH), 1.55
(CH2), 21.5 (CH2), 13.8 (CH3). 19F NMR (400 MHz, CD3CN): dF (1H, m, CH2–CHH), 1.22 (3H, d, J ¼ 6.4 Hz, CH3), 1.19–1.03 (3H,
ꢂ127.4. MS-EI m/z, 193.2 (M+ ꢂ Fꢂ). EI-HRMS (M+ ꢂ Fꢂ) m, CH2–CHH). MS-EI m/z 215.1 (M+), EI-HRMS (M+) C14H17N1O
C
12H21N2 found 193.1722, calculated 193.1705.
found 215.1327, calculated 215.1310.
4.2.2. 4-(Dimethylamino)-1-heptylpyridin-1-ium uoride
4.3.5. 8-Chloro-4a-methyl-2,3,4,4a-tetrahydro-1H-carba-
(3). Yellow oil, (180 mg, 75%), IR (nmax, cmꢂ1): (liquid, CHCl3) zole (6e). Yield 76% 1H NMR (400 MHz, DMSO-d6): dH 7.38 (1H,
3442, 2929, 1650, 1569, 1403, 1175, 833. 1H NMR (400 MHz, d, J ¼ 7.2 Hz, ArH), 7.34 (1H, d, J ¼ 8 Hz, ArH), 7.19 (1H, t, J ¼
DMSO-d6): dH 8.31 (2H, d, J ¼ 8.0 Hz, ArH), 7.02 (2H, d, J ¼ 7.6 Hz, ArH), 2.71 (1H, app d, J ¼ 12.8 Hz, CHH), 2.66–2.58 (1H,
7.6 Hz, ArH), 4.15 (2H, t, J ¼ 7.0 Hz, CH2), 3.17 (6H, s, C(CH3)2), m, CHH), 2.27 (1H, app d, J ¼ 13.2 Hz, CHH), 2.13 (1H, app d, J ¼
1.75 (2H, quint, J ¼ 7.4 Hz, CH2), 1.27–1.19 (8H, m, (CH2)4), 0.85 13.2 Hz, CHH), 1.80–1.72 (1H, m, CHH–CH2), 1.60 (1H, app d, J
(3H, t, J ¼ 6.6 Hz, CH3); 13C NMR (100 MHz, DMSO-d6): dC 155.8 ¼ 13.6 Hz, CHH–CH2), 1.34–1.26 (1H, m, CH2–CHH), 1.27
(C), 142.1 (CH ꢄ2), 107.7 (CH ꢄ2), 56.6 (CH2), 39.7 (CH3 ꢄ2), (3H, s, CH3), 1.01 (1H, td, J ¼ 13.2, 4 Hz, CH2–CHH). MS-EI m/z
31.1 (CH2), 30.3 (CH2), 28.1 (CH2), 25.3 (CH2), 21.9 (CH2), 13.8 219.1 (M+), 221.1, EI-HRMS (M+) C13H14N1Cl found 219.0811,
(CH3). 19F NMR (400 MHz, CD3CN): dF ꢂ127.5. MS-ESI m/z (%), calculated 219.0815.
34204 | RSC Adv., 2017, 7, 34197–34207
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4.3.6. 6-Cyano-2,3,4,9-tetrahydro-1H-carbazole (6f). Yield
RSC Advances
4.4.4. 5-(40-Bromophenyl)-1H-tetrazole (20).43 68% 1H NMR
60% 1H NMR (300 MHz, DMSO-d6): dH 11.27 (1H, s, NH), 7.83 (400 MHz, DMSO-d6): dH 7.96 (2H, d, J ¼ 8.4 Hz, ArH), 7.79 (2H,
(1H, s, ArH), 7.38 (1H, d, J ¼ 8.4 Hz, ArH), 7.31 (1H, dd, J ¼ d, J ¼ 8.4 Hz, ArH); MS-EI m/z 223 (M+), 225.
8.4, 1.5 Hz, ArH), 2.69 (2H, app t, J ¼ 6.4 Hz, CH2), 2.64 (2H, t,
4.4.5. 5-(40-Methoxyphenyl)-1H-tetrazole (21).45 70% 1H
J ¼ 5.7 Hz, CH2), 1.81–1.74 (4H, m, CH2–CH2). MS-EI m/z NMR (400 MHz, DMSO-d6): dH 7.97 (2H, d, J ¼ 8.8 Hz, ArH), 7.14
196.1 (M+).
4.3.7. 7-Bromo-4a-methyl-2,3,4,4a-tetrahydro-1H-carbazole
(2H, d, J ¼ 8.8 Hz, ArH), 3.83 (3H, s, OCH3); MS-EI m/z 176 (M+).
4.4.6. 5-(40-Fluorophenyl)-1H-tetrazole (22).46 58% 1H NMR
(6g). Yield 55% 1H NMR (400 MHz, DMSO-d6): dH 7.65 (1H, s J ¼ (400 MHz, DMSO-d6): dH 8.07 (2H, dd, J ¼ 8.8, 5.6 Hz, ArH), 7.45
7.6 Hz, ArH), 7.39–7.34 (2H, m, ArH), 7.64 (1H, d, J ¼ 8 Hz, ArH), (2H, t, J ¼ 8.8 Hz, ArH); MS-EI m/z 164 (M+).
2.68–2.57 (2H, m, CH2), 2.28 (1H, app dd, J ¼ 12.8, 2.4 Hz, CHH),
2.12 (1H, app d, J ¼ 12.8 Hz, CHH), 1.79–1.71 (1H, m, CHH–
4.5. Theoretical methods
CH2), 1.60 (1H, app d, J ¼ 14 Hz, CHH–CH2), 1.31–1.21 (CHH–
CH2), 1.24 (3H, s, CH3), 0.97 (1H, td, J ¼ 13.6, 4 Hz, CH2–CHH).
A similar protocol was followed for the theoretical investigation
of DMAP based ionic liquids that was successfully applied to
MS-EI m/z 263.2 (M+), 265.2, EI-HRMS (M+) C13H14N1Br found
quinolone based ionic uoride salts (QuFs).36
263.0300, calculated 263.0310.
4.3.8. 6-Methoxy-2,2-dimethyl-2,3-dihydro-1H-carbazol-4-
(9H)-one (6h).42 Yield 17% 1H NMR (400 MHz, DMSO-d6): dH
11.66 (1H, s, NH), 7.43 (1H, d, J ¼ 2.4 Hz, ArH), 7.25 (1H, d, J ¼
8.8 Hz, ArH), 6.76 (1H, t, J ¼ 8.8 Hz, ArH), 3.75 (3H, s, OCH3),
2.80 (2H, s, CH2), 2.30 (2H, s, CH2), 1.07 (6H, s, (CH3)2).
4.5.1. Binding energy calculations. Prior to binding energy
calculations, both DMAP (2) and (3) derivatives were optimized
at the Hartree–Fock level of theory using 6-311G(d,p) basis sets
for all atoms without the application of symmetry constraints.
The binding energies of both derivatives were calculated at MP2
level of theory and 6-311G(d,p) basis sets were utilized for all
atoms in order to evaluate thermal stabilities of these
compounds. All ab initio calculations were performed using
4.4. A general procedure for phenyl 1H-tetrazole synthesis
To an oven dried micro reaction vessel corresponding benzo- Gaussian 09 soware.47
nitrile (1 mmol, 1 equiv.), trimethylsilyl azide (3 mmol, 3 equiv.)
4.5.2. Molecular dynamics simulations. The initial cong-
and DMAP-IL 5 (0.3 equiv.) were added at room temperature uration of the simulation boxes of DMAP (2) and (3) ionic
and then capped with septum for reaction. The vessel with liquids were prepared using the optimized structures of these
reaction mixture was heated at 110–115 ꢀC for 24 h until the derivatives as shown Fig. 9.
complete consumption of starting material, judged thin layer
Both DMAP derivatives were modeled with Generalized
chromatography. On cooling the reaction mixture was diluted Amber Force Field (GAFF)48 and restrained electrostatic poten-
with EtOAc (20 mL) and shaked with 1–2 M HCl (20 mL) in tial (RESP) charges49,50 were obtained. Simulation boxes con-
separating funnel. Organic layer was separated and aqueous sisting of 200 ion pairs of DMAP derivatives were constructed in
layer was further extracted with EtOAc (15 mL). The combined dened regions of space using Packmol program.51
organic layers were dried with MgSO4, lter and evaporated in
Prior to performing MD simulations, both systems were
vacuo to get the crude material. For purication silica gel subjected to 10 000 steps of energy minimizations which were
column chromatography with eluents EtOAc/hexane (1 : 1) to then followed by NVT equilibration for 15 ns. Aerwards, both
get the pure 1H-tetrazoles (17–22) as off-white to white solids in systems were subjected to production MD for 40 ns including
48–78% yield.
NPT equilibration and sampling of simulation trajectories. All
1
4.4.1. 5-Phenyl-1H-tetrazole (17). 48% H NMR (400 MHz, bonds including hydrogen bonds were kept, thus enabling to
DMSO-d6): dH 8.04–8.02 (2H, m, ArH), 7.60–7.58 (3H, m, ArH); use time step of 1.0 fs throughout the simulation. Long range
MS-EI m/z 146 (M+). The data is identical to those previously electrostatic interactions were treated by applying particle mesh
reported.15
Ewald algorithm and for non-bonded interactions, a cutoff
1
4.4.2. 5-(40-Methylphenyl)-1H-tetrazole (18).43 78% H NMR value of 8.0 A was used. The temperature was controlled at ꢃ298
˚
(400 MHz, DMSO-d6): dH 7.91 (2H, d, J ¼ 8.4 Hz, ArH), 7.39 (2H, K using Langevin thermostat with collision frequency of 5.0
d, J ¼ 8.0 Hz, ArH), 2.38 (3H, s, CH3); MS-EI m/z 160 (M+).
psꢂ1, and pressure coupling algorithm with a relaxation time pf
4.4.3. 5-(40-Chlorophenyl)-1H-tetrazole (19).43,44 59% 1H 1.0 ps was employed to maintain the pressure. Both MD simu-
NMR (400 MHz, DMSO-d6): dH 8.06 (2H, d, J ¼ 8.4 Hz, ArH), 7.68 lation were performed using SANDER module of AMBER-
(2H, d, J ¼ 8.4 Hz, ArH); MS-EI m/z 180 (M+).
TOOLS17 whereas analysis of simulation trajectories were
Fig. 9 HF optimized structures of DMAP (2) and (3) ionic liquids.
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carried out by the CPPTRAJ module of AMBERTOOLS17.52 For 23 R. N. Butler, in Comprehensive heterocyclic chemistry II, ed. A.
the visualization of simulation trajectories, VMD53 were used.
R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon,
Oxford, 1996, pp. 621–678.
24 P. N. Gaponik, S. V. Voitekhovich and O. A. Ivashkevich,
Russ. Chem. Rev., 2006, 75, 507.
Conflict of interest
25 R. J. Herr, Bioorg. Med. Chem., 2002, 10, 3379–3393.
26 A. Sarvary and A. Maleki, Molec. Divers., 2015, 19, 189–212.
27 A. Maleki and A. Sarvary, RSC Adv., 2015, 5, 60938–60955.
28 Z. P. Demko and K. B. Sharpless, Angew. Chem., Int. Ed.,
2002, 41, 2110–2113.
29 Z. P. Demko and K. B. Sharpless, J. Org. Chem., 2001, 66,
7945–7950.
30 S. Vorona, T. Artamonova, Y. Zevatskii and L. Myznikov,
Synthesis, 2014, 46, 781–786.
The authors have declared no conict of interest.
Acknowledgements
The authors are thankful to Higher Education Commission
(HEC) Pakistan for providing nancial support under “National
Research Program for Universities” to Project No. 4732.
31 S. Hajra, D. Sinha and M. Bhowmick, J. Org. Chem., 2007, 72,
1852–1855.
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