Bile acid hydrazides: Gelation, structural, physical and spectroscopic properties

Article abstract of DOI:10.1039/c4nj01352b

Synthesis and gelation properties of a series of novel bile acid hydrazides are presented. These compounds are found to undergo self-assembly leading to organogelation in certain organic solvents. Compound 1 was found to be the most "effective" gelator in this series. The properties of this gel have been thoroughly investigated by conventional methods typical for molecular gel studies. Sol-gel transition temperature (T_g) of chloroform gels of compounds 1 and 3 was found to increase with increase in the chain length. Sol-gel transition was probed using the isothermal time test and results show that there is instantaneous increase in both the moduli after shear melting, which suggests that the kinetics of formation of the network was very fast. IR and NMR studies revealed hydrogen bonding between amidic carbonyl in the side chain and hydroxyl groups of cholic acid.

Full text of DOI:10.1039/c4nj01352b

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Bile acid hydrazides: gelation, structural, physical
and spectroscopic properties†
Cite this: New J. Chem., 2015,
39, 453
Vandana S. Pore,*a Sandip G. Agalave,a Shrikant G. Pharande,a Prashant A. Patilb
and Amol S. Kotmalea
Synthesis and gelation properties of a series of novel bile acid hydrazides are presented. These
compounds are found to undergo self-assembly leading to organogelation in certain organic solvents.
Compound 1 was found to be the most ‘‘effective’’ gelator in this series. The properties of this gel have
been thoroughly investigated by conventional methods typical for molecular gel studies. Sol–gel transition
temperature (Tg) of chloroform gels of compounds 1 and 3 was found to increase with increase in the
chain length. Sol–gel transition was probed using the isothermal time test and results show that there
is instantaneous increase in both the moduli after shear melting, which suggests that the kinetics of
formation of the network was very fast. IR and NMR studies revealed hydrogen bonding between amidic
carbonyl in the side chain and hydroxyl groups of cholic acid.
Received (in Montpellier, France)
11th August 2014,
Accepted 27th October 2014
DOI: 10.1039/c4nj01352b
www.rsc.org/njc
with aliphatic or aromatic molecules with a large surface area.
Many efficient gelators of organic solvents (organogelators) and
1. Introduction
Synthesis of supramolecular assemblies is the fundamental water (hydrogelators) have actually been prepared by their
step to new materials.1–3 In recent years low molecular mass structural combination.10
organic molecules, capable of gelation with various liquids,
Recent advances in the field of steroidal supramolecular gels
have attracted considerable attention.4 The self-assembly of and their potential applications have been summarized by
11
¨
small organic molecules to form three-dimensional networks Sievanen and co-workers. Bile acids and their derivatives,
creates matrices that can hold solvent molecules, thereby because of their unique structural features, represent fascinating
forming gels. This gives systems with new properties based on a compounds from a supramolecular point of view.12 Bile acids are
three-dimensional network held together by various multiple non- natural compounds consisting of a facially amphiphilic steroid
covalent interactions such as hydrogen bonding, hydrophobic nucleus with a hydrophobic b-side due to angular methyl groups
interaction, dispersion forces and p–p stacking. There are several and a hydrophilic a-side due to hydroxyl groups. The amphiphili-
building blocks known for their good gelation properties such as city, structure rigidity and acid–base characteristics of the bile
steroids, saccharides, nucleobases, porphyrins etc. Sol–gel systems acid molecules make them useful building blocks in biomedical
have been used as active components of sensors, drug delivery applications. Furthermore, the overall polarity profile of these
systems, membranes, etc. due to their interesting properties.5–7 compounds can be tailored and the self-assembling charac-
Evolution in Low Molecular weight Organo Gel (LMOG) research teristics adjusted, which makes them potential components
paves the way for its developments in high-tech materials and of supramolecular gels. Numerous organo- and hydrogels
biomaterials.8,9
composed of bile acids/salts and their derivatives have been
Design of new molecules capable of self-assembly leading to reported and investigated.13 Recently, there was a review article
gelation is very complicated due to the challenging specifica- by Maitra and Sajisha on functional soft materials synthesized
tion of conditions and structural requirements for a gelator. in bile acid-based supramolecular hydrogel matrices.14 Dukh and
Structural features known to promote one-dimensional aggregation co-workers have synthesized bile acid amides–phenanthroline
include amidic, carbamate, urea or oxalamide groups combined hybrids and studied their gelation and metal co-ordination
properties.15 Noponen et al. have reported synthesis and gelation
a Organic Chemistry Division, CSIR-National Chemical Laboratory,
Dr. Homi Bhabha Road, Pashan, Pune 411 008, India. E-mail: vs.pore@ncl.res.in;
Fax: +91 2025902629; Tel: +91 2025902320
properties of bile acid–amino acid conjugates.16 There is report
on cholic acid hydrazide-modified dextran nanoparticles for
in vitro drug release.17 Lotowski and Guzmanski have synthesized
cholic acid dimers with hydrazide as a spacer.18 Hydrazones
prepared from bile acid hydrazide have been reported to show
good antimicrobial activity.19
b Polymer Science and Engineering Division, CSIR-National Chemical Laboratory,
Dr. Homi Bhabha Road, Pashan, Pune 411 008, India
† Electronic supplementary information (ESI) available: Experimental details,
spectroscopic data and SEM images. See DOI: 10.1039/c4nj01352b
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Hydrazine is a useful building block in organic synthesis
of pharmaceuticals and pesticides. The antitubercular drug
isoniazid contains the hydrazine moiety. There is a recent report
on supramolecular organogels based on a hydrazide derivatives.20
Very recently aroylhydrazine–amide receptors with a hydrazine
spacer have been reported as novel colorimetric chemosensors.21
Polymers containing the hydrazine spacer have been synthesized
and used for encapsulation of anticancer drugs.22
Bile acid derived gelators can interact specifically with their
transporter proteins and/or possess specific functions such as
controlled and organ targeted drug release via enterohepatic
circulation. Alkyl and amide derivatives of bile acids are
potential gelating agents.13a,c–e In continuation of our work on
bile acids,23 we wish to report here synthesis of novel bile acid
conjugates containing the hydrazine spacer. Interestingly, few
conjugates showed sol–gel transition in few organic solvents. One
of these gels has been investigated for structural, thermal and
morphological studies. It was hypothesized that the synergic
effect of both moieties of the conjugate may lead to the formation
of a new kind of supramolecular structures.
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Table 1 Gelation properties of 2% (w/v) solutions of compounds 1–6a in
various solvents
Results
Solvent
1
2
3
4
5
6
Methanol
DCM
CHCl3
CCl4
THF
CH3CN
Benzene
Toluene
n-Hexane
DMF–H2O (1 : 1)
S
S
C
C
C
S
I
I
I
I
S
S
I
S
C
C
I
S
P
I
I
C
S
S
S
I
P
I
S
I
I
I
I
S
TGb
TGb
TGb
S
WG
P
C
S
I
I
I
I
S
TGc
WGc
S
S
S
CG
CG
I
TGc
TGc
I
P
S
TGb, transparent gel (at room temperature); TGc, transparent gel (after
heating); I, insoluble; S, solution; CG, cloudy gel (after heating); P,
precipitate, C, coagulation; WGb, weak gel (at room temperature); WGc,
weak gel (after heating at boiling temperature of solvent).
a
observed that the molecule with shorter chain length than
compound 1 (compound 2) did not form gel with any of the
tested solvents while compounds having longer chain length
than compound 1 (compound 3) formed gel in chloroform or
carbon tetrachloride solution after heating at boiling tempera-
ture of the solvent. Introduction of an aromatic group in the
alkyl tail deteriorates the gelation ability. The compound con-
taining different substitution groups in the aromatic ring also
behaved differently. The compound with the 4-chlorobenzoyl
moiety (compound 5) could form weak gel only in dichloro-
methane while other aromatic compounds such as 4 and 6 did
not give gels. The driving force for aggregation of bile acid
gelators is hydrogen bonding between the amide group and the
hydroxyl groups and also intermolecular hydrogen bonding
between amidic carbonyls of one molecule with amidic NH of
another molecule. It is reported that compounds lacking one of
these groups did not produce gels in some solvents.13a There is a
report in which compounds lacking all the hydroxyl groups due
to formation of ketones gave organogels.13d There is another
report in which lithocholic acid having one and cholic acid
having three hydroxy groups formed gels but deoxycholic acid
with two hydroxy groups did not give gels.13e We also found that
deoxycholic acid in which hydroxyl group at C-7 is absent, did
not give gel in any of the tested solvents.
2. Results and discussion
A series of bile acid hydrazides was synthesized by reacting cholic
acid with respective hydrazides using the literature procedure24
with some modifications (Fig. 1). All the compounds were obtained
in moderate chemical yields and were characterized by conven-
tional physical and spectroscopic methods. The attempts to obtain
single crystals of these compounds remained unsuccessful. This
may be due to the highly amorphous nature of these molecules and
hence the melting points were not sharp. All the synthesized
compounds were tested for their gelation behaviour in 10 different
solvents and the results are summarized in Table 1.
Three out of six compounds were found to form gels depending
upon the solvent. Gels were obtained from 2% (w/v) solutions and
appeared as opaque (cloudy) or transparent or weak depending on
the compound and solvent in question. Regarding the number of
solvents gelled, compound 1 seems to be the most ‘‘effective’’
gelator in this series. It formed gel in five different solvents. Hence
further study was carried out on compound 1.
Gelation ability, efficiency and properties change dramatically
with small structural variations in the gelator molecule. It was
Interestingly, gel to sol phase transition can be induced by
shaking the gel vigorously, in contrast, resting the solution
results in gelation again (Fig. 2). Ultrasonic treatment is another
effective way to trigger the phase transition of the gel. In this case,
Fig. 1 Chemical structures of compounds 1–6.
Fig. 2 Phase transition of gel of compound 1.
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the liquid is a viscous suspension, rather than a clear solution
(Fig. 2). Melting points of 2% w/v benzene and chloroform
gels of compound 1 and 3 were determined with Differential
Scanning Calorimetry (DSC). Benzene gels of compounds 1 and
3 showed two endothermic peaks (please see DSC figure in
ESI†). The first endothermic peak at around 8 1C is due to the
melting point of benzene and the second endothermic peak at
around 84 1C and 87 1C is due to melting of gel network
structures in compounds 1 and 3 respectively. The chloroform
gel of compound 5 was found to be unstable and it was not
possible to find its sol–gel transition temperature. Sol–gel
transition temperatures (Tg) of the chloroform gel of compound
1 show two peaks at 65 and 71 1C while that of compound 3
shows a single peak at 68 1C. Melting point of the chloroform
gel of compound 1 was also determined by visually monitoring
the flow of gel in a thermally controlled bath13i and was found to
be 62 1C. It is worth mentioning that the benzene and chloroform
gels are so stable that their melting does not occur below the
boiling point of the pure solvents. As expected, the gel is thermo-
reversible in nature. Gel melts upon heating and forms upon
Fig. 3 E-SEM images of gels of 2% (w/v) compound 1 (A) in benzene;
cooling the solution (Fig. 2). This shear-stress-triggered reversible (B) in CHCl3; E-SEM images of xerogels of 2% (w/v) compound 1 (C) in
benzene; (D) in CHCl3 (scale bars 10 mm).
sol–gel phase transition phenomenon was further studied by
rheological techniques (Fig. 6 to 9).
band at 3196 cmꢀ1 while that in its gel form showed two peaks
2.1. Morphology
The morphology of gels derived from compound 1 in two at 3373 and 3251 cmꢀ1. Amide carbonyl in the solution phase
different solvents (benzene and chloroform) was investigated by appeared at 1626 cmꢀ1 while that of the gel appeared at
environmental scanning electron microscopy (E-SEM). (a) Gels in 1640 cmꢀ1. This shift in amide frequency clearly demonstrated
benzene and chloroform, (b) xerogels obtained after sonication, that upon gelation there is hydrogen bonding of amide carbonyl.
(c) xerogels obtained after complete drying and (d) dried sample This conclusion was confirmed by the results obtained from
were studied. The influence of the solvent on gel formation is well concentration- and temperature-dependent 1H NMR studies sug-
recognized as depending on the solvent, it leads to different gesting that not only the bile acid units, but also the hydrogen
shapes of the aggregates giving different microstructures (see bonds between adjacent linkers of the gelator plays an important
ESI†). The E-SEM micrograph did not reveal any regular fibrous role in the formation of the gel network.
1
structures. It only showed three-dimensional structures con-
2.2.2. Variable temperature H NMR study. Earlier studies
structed from thin micro flakes of different sizes and mostly of amido alcohol derivatives of bile acids have demonstrated
rounded shapes in benzene gel (Fig. 3, and ESI†) suggesting that that the amide bond and several hydroxyl groups are essential
the gel microstructure was very fragile and collapsed upon for hydrogen bonding.13f The spatial orientations of these groups
solvent evaporation as well as due to sonication. E-SEM analysis also play an important role in gelation along with intermolecular
of chloroform gels showed that fibers driven by weak inter- hydrophobic effects, mostly between steroidal ring systems, and
molecular interactions were formed, as can be seen from Fig. 3. the amide. In order to investigate the hydrogen bond interactions
It can be suggested that hydrogen bonding interactions may be of hydroxyl groups and amide nitrogen protons involved in the gel
responsible for the fiber formation, as the molecules contain an formation, variable-temperature (25–45 1C) 1H NMR spectra of the
amide group and hydroxyl groups. Such type of intermolecular gel in CDCl3-(2% w/v) of compound 1 were recorded. For com-
hydrogen bonding has been observed in previous studies of pound 1 (Fig. 4), in the gel state at ambient temperature 1H NMR
gelation properties of bile acid amides.13a Hydrogen bonding signals were appeared as broad signals (spectrum at 25 1C). By
may be one of the driving forces, but also hydrophobic as well as heating the sample in 5 1C steps, the signals became sharper.
van der Waals interactions must be taken into account. However With an increase in the temperature, amidic protons at 10.02, 8.98
it is not fully understood how these fibers are constructed from and hydroxy proton at 2.95 ppm showed a slight up field chemical
the gelator molecules.
shift. This is due to loss of inter molecular hydrogen bonding with
increase in temperature and slow melting of gel. At higher
temperature (above 35 1C) new peaks appeared at the down field
2.2. Spectroscopy
2.2.1. FTIR Study. FT-IR studies with compound 1 were ranges. This may be due to rotational isomers of two amides.
conducted in order to check hydrogen bonding. The region
2.2.3. Variable concentration 1H NMR study. A similar
3000–3500 cmꢀ1 showed bands for OH and NH stretching experiment was carried out for compound 1 by using concen-
1
vibrations (see ESI†). IR in the solution form showed a broad tration dependent H NMR spectra (Fig. 5). It was found that
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Fig. 6 Storage and loss moduli as a function of strain%.
Fig. 4 Variable-temperature 1H NMR of compound 1 (2% w/v in CDCl3).
Fig. 7 Shear stress ramp test.
2.3.2. Stress ramp test. Fig. 7 shows G0 and G00 as a function
of shear stress. Stress ramp test was performed in order to find
yield stress of the gel.26 The oscillatory stress ramp test on gelled
samples was performed at 1 Hz frequency with shear stress
ranging from 0.01 to 1000 Pa at 15 1C. In the gel state, G0 4 G00
showed solid like behaviour. As shear stress was increased, the
G0 and G00 started dropping and G00 crosses over G0 indicating
liquid like behaviour (i.e. shear melting of network structure
formed during gelation). The gelled sample showed shear yield-
ing behaviour at shear stress 5 Pa.
Fig. 5 Concentration dependent 1H NMR of compound 1.
with an increase in the concentration of solution from 0.2% w/v
to 2.5% w/v, the chemical shifts of the NH and OH protons to
higher ppm values. Up to 2% there is slight chemical shift in OH
proton at 2.95 and then there is large chemical shift when the
concentration is 2.5% where it is in the gel form clearly indicating
that hydrogen bonding plays a role in the self-assembly.
2.3. Rheology
2.3.3. Isothermal time test. The results of shear melting
All the experiments were carried out on 2% w/v of the benzene and small amplitude oscillatory strain isothermal time test are
gel of compound 1 at 15 1C. shown in Fig. 8. This test was performed in two intervals. In the
2.3.1. Strain sweep test. The linear viscoelastic regime of first interval, stress ramp test in oscillatory mode above yield
the gel was found using a strain sweep test.25 The strain sweep stress (5 Pa) was performed in order to melt the gel in the cup
test was carried out at a constant angular frequency of 10 rad sꢀ1 and in the second interval, the time dependent rise in storage
and strain amplitude ranging from 0.01 to 100% at 15 1C.
modulus and loss modulus was monitored as a function of time
The main purpose of this test is to identify the linear under oscillatory strain in the linear viscoelastic regime. This
viscoelastic regime for the gel. All further experiments were dynamic small amplitude oscillatory shear test is widely used to
performed in linear viscoelastic range. The results of strain study the time evolution growth of the network structure.27–31
sweep tests are shown in Fig. 6. At low strain values, storage In the first interval, initial state gel showed solid like behaviour
modulus (G0) was higher than loss modulus (G00) indicating the with G0 higher than G00 and as the gel yielded, there was a
solid like behaviour of the gel. As the strain percentage was crossover between G0 and G00 suggesting shear melting of the
increased to 3%, the storage modulus and loss modulus started network structure formed during gelation. The high shear stress
dropping, indicating the yielding of the gel and after 12% causes breakage of network structure formed during gelation.
strain, G00 crossed over G0 (G00 4 G0) indicating the liquid like The gel was melted in the cup to convert it to sol (G00 4 G0).
behaviour.
The second interval showed sol to gel transition at 15 1C.
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in different solvents. These are new supramolecular gelators
with potential high-tech applications. IR and NMR study of
these gels confirm intermolecular hydrogen bonding due to OH
and NH protons which is responsible for gelation. Gel shows
solid like behaviour over the entire frequency range. Sol gel
transition was probed using an isothermal time test and results
show that instantaneous rise in both the moduli after shear
melting suggesting that the kinetics of formation of the network is
very fast. The DSC study shows that benzene gel to sol conversion
takes place at 84 1C while chloroform gel to sol conversion takes
place at 65 1C both of which are above the boiling points of their
solvents. It is very interesting and uncommon that this type of small
organogelators can gelate some solvents at room temperature. The
potential applications of these gels are under further investigation.
These molecules are under biological testing, and as bile acid
conjugates, they are expected to show good biological activity.
Fig. 8 Shear melting and the isothermal time test.
4. Experimental section
4.1. General methods
All chemicals were obtained from commercial sources and used as
received without further purification. All the reactions were carried
out under a nitrogen atmosphere. Column chromatography was
carried out by using silica gel (60–120 mm, Merck). All reactions
were monitored by TLC with silica gel coated plates; spots were
visualized by UV light and/or with dipping in a phosphomolybdic
acid solution and charring on a hot plate. All the liquid state
1D-NMR spectra (1H, 13C NMR) were recorded in CDCl3 (for com-
pound 1), CDCl3 + CD3OD (for compounds 5 and 6) and CD3OD
(for compounds 2, 3 and 4) on AC 200 MHz and AV-500 MHz
Bruker NMR spectrometers. Chemical shifts are reported in ppm.
Coupling constants J are reported in Hz. The temperature depen-
Fig. 9 Storage and loss moduli as a function of frequency.
1
dent H NMR experiments for compound 1 (2% w/v) were carried
Isothermal time test results showed that both moduli grow out in CDCl3 by increasing temperature in 5 steps (25 1C, 30 1C,
instantaneously with G0 higher than G00 indicating transition 35 1C, 40 1C and 45 1C successively) and for concentration depen-
1
from sol (G00 4G0) to gel (G0 4 G00) state. The initial instantaneous dent H NMR experiments for compound 1 were carried out in
rise in G0 and G00 indicates that kinetics of network formation was CDCl3 by using different NMR tubes of concentrations 0.2%, 0.4%,
very fast at this temperature. After rapid rise, both the moduli 0.8%, 1.2%, 1.7% and 2.5%. The 1H chemical shifts were referenced
grow slowly and both the moduli are comparable to initial to TMS as an internal standard. Infrared (IR) spectra were recorded
moduli in interval 1.
on a liquid cell with KBr plates. Only diagnostic bands are reported
2.3.4. Frequency sweep test. Frequency sweep test was carried on a cmꢀ1 scale. The ESI ion trap mass spectra were measured by a
out at a constant strain amplitude of 0.05% and angular frequency Finnigan MAT LCQ mass spectrometer. The HRMS spectra were
ranging from 0.01 to 628 rad sꢀ1 at 15 1C. Typically, gels shows acquired on a thermoscientific Q exactive spectrometer. An environ-
G0 4 G00 in the frequency sweep experiment. The G0 shows very mental scanning electron microscope Quanta 200 3D by FEI was
weak frequency dependence in gels with minima in G00 in the used for obtaining morphology of gels. Rheological properties of
frequency sweep experiment.32,33 The gel shows solid like gels were studied using a MCR 301 Rheometer (Anton Paar) with a
behaviour with G0 4 than G00 over the entire frequency range cup and bob geometry. The gel was loaded in a cup and sufficient
(Fig. 9). The gel shows minima in G00 while G0 and G00 are dependent delay time was given in order to form gel in the cup. A DSC study of
on the frequency. Such type of behaviour is typically observed for the gel sample was performed on TA instruments Q 100 Differential
weakly associated gels.34
Scanning Calorimeter. A sealed pan was used for the measurement.
4.2. Synthesis
3. Conclusions
Cholic acid hydrazides were synthesized by reacting cholic acid
In the present work, we have presented novel cholic acid with respective hydrazides using a literature procedure with
hydrazides gelators which form thermoreversible organogels some modifications (Fig. 1).24
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To a solution of cholic acid (1 mmol), acid hydrazide (1 mmol), 3.80 (s, 1H), 3.36 (m, 1H), 1.05 (d, J = 6.1 Hz, 3H), 0.90 (s, 3H),
and EDCI (1.2 mmol) dissolved in DCM (10 mL), DMAP (1.2 mmol) 0.71 (s, 3H); dC (125 MHz, CDCl3 + MEOD) 175.9, 168.0, 139.3,
was added in one portion at room temperature. The reaction 132.3, 130.3 (2C), 129.8 (2C), 74.0, 72.8, 69.0, 48.0, 47.5, 43.2, 43.0,
mixture was stirred at room temperature for 8 h. After completion 41.0, 40.4, 36.8, 36.5, 35.9, 35.8, 32.8, 31.8, 31.2, 30.7, 29.6, 28.7,
of reaction, the reaction mixture was extracted with 10% methanol 27.9, 24.2, 23.1, 17.7, 14.4, 13.0; HRMS calculated for C31H45O5N2-
in DCM. The organic layer was washed with saturated aqueous ClNa 583.2905; found 583.2909.
NaHCO3, brine, and was dried over Na2SO4. The crude product
upon purification by column chromatography on silica gel yielded trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-
4.2.6. 4-Nitro-N0-((4R)-4-((3R,5S,7R,10S,12S,13R,17R)-3,7,12-
the pure product.
phenanthren-17-yl)pentanoyl)benzo hydrazide (6). 46%; mp
4.2.1. N0-((4R)-4-((3R,5S,7R,10S,12S,13R,17R)-3,7,12-Trihydroxy- decomposes above 162 1C; nmax/cmꢀ1 3415, 3258, 3050, 2935,
10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17- 2862, 1698, 1662 and 1540; dH (500 MHz, CDCl3 + MEOD) 8.22
yl)pentanoyl)decane hydrazide (1). 57%; mp 109–110 1C; (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 3.91 (s, 1H), 3.77 (s,
n
max/cmꢀ1 3405, 3269, 2922, 2854, 1694 and 1651; dH (500 MHz; 1H), 3.34 (m, 1H), 0.96 (d, J = 6.4 Hz, 3H), 0.82 (s, 3H), 0.62 (s,
CDCl3; Me4Si) 10.02 (br s, 1H), 8.98 (br s, 1H), 4.02 (br s, 1H), 3.85 3H); dC (125 MHz, CDCl3 + MEOD) 173.5, 164.3, 149.7, 137.5,
(s, 1H), 3.43 (s, 1H), 2.95 (b, 2H, OH), 1.04 (d, 3H), 0.89 (m, 6H), 128.7 (2C), 123.5 (2C), 72.9, 71.3, 68.1, 46.1, 45.7, 41.4, 41.2,
0.69 (s, 3H); dC (125 MHz; MEOD) 175.6, 175.0, 74.0, 72.8, 69.0, 39.1, 38.9, 35.0, 34.5, 34.3, 30.9, 29.7, 29.6, 29.5, 27.8, 27.3, 26.1,
48.0, 47.5, 43.1, 42.9, 41.0, 40.4, 36.8, 36.5, 35.9, 34.7, 33.0, 32.7, 23.0, 22.2, 17.0, 12.1; HRMS calculated for C31H45O7N3Na
31.7, 31.1, 30.7, 30.5, 30.4, 30.2, 29.5, 28.6, 27.8, 26.5, 24.2, 23.7, 594.3146; found 594.3120.
23.1, 17.7, 14.4, 13.0; HRMS calculated for C34H60O5N2Na
599.4392; found 599.4394.
4.3. Gelation test
4.2.2. N0((4R)-4-((3R,5S,7R,10S,12S,13R,17R)-3,7,12-Trihydroxy-
10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-
yl)pentanoyl)pentanehydrazide (2). 26%; mp 171–173 1C;
In the gelation experiments, a known weight (2 wt%) of a potential
gelator and a measured aliquot of liquid were placed into a capped
glass sample vial and the system was heated in an oil bath until the
solid was dissolved, then, the solution was cooled slowly to room
temperature in air, and finally the sample vial was inverted to look
at if the solution inside could still flow. The sample was defined as
a gel, if no flow was observed. When a gel was formed at this stage,
it was denoted as ‘‘G’’. It is to be noted that some transparent gels
can be obtained at room temperature, which were denoted as
‘‘TG’’. In some cases, a gel remains cloudy so this kind of system
has been referred to as ‘‘cloudy gels (CG)’’. For systems in which
only solution remained until the end of the tests, they were referred
to as solution (S). When the gelator of a system appeared as a
precipitate or crystals, the system was denoted as ‘‘P’’. The system,
in which the potential gelator could not be dissolved even at the
boiling point of the solvent, was called an insoluble system (I)
(please see Table 1). Gelator 1 dissolved in DCM, CHCl3 and CCl4 at
room temperature and forms transparent gel after some time while
gelator 1 dissolved in benzene and toluene near to their boiling
point and forms cloudy gel upon cooling solution. Gelator 3 forms
clear solution upon heating the solution to the boiling point.
n
max/cmꢀ1 3408, 3265, 2920, 2856, 1690 and 1652; dH (200 MHz;
CD3OD) 5.47 (s, 1H), 3.94 (br s, 1H), 3.78 (br s, 1H), 3.18 (s,
2 H),2.72 (s, 2H), 1.01–0.91 (m, 9H), 0.70 (s, 3H); dC (125 MHz;
CD3OD) 174.5, 72.9, 71.6, 70.7, 50.8, 43.8, 42.7, 41.1, 38.5, 38.3,
35.1, 33.5, 31.4, 30.5, 29.7, 28.8, 28.4, 28.1, 27.4, 27.0, 23.2, 22.4,
17.6, 12.4; m/z 546.2 (M + 39 for K).
4.2.3. N0-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-
Trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-
phenanthren-17-yl)pentanoyl)palmito hydrazide (3). 39%; mp
117–118 1C; nmax/cmꢀ1 3410, 3264, 2923, 2856, 1690 and 1654;
dH (500 MHz; MeOD) 3.95 (s, 1H), 3.83 (s, 1H), 3.62 (s, 1H), 1.02
(d, 3H), 0.90 (m, 6H), 0.69 (s, 3H); dC (125 MHz; MEOD) 175.8,
175.3, 74.2, 73.0, 69.2, 48.1, 47.6, 43.3, 43.1, 41.1, 40.6, 36.9,
36.6, 36.0, 34.9, 33.2, 32.9, 31.8, 31.3, 30.9, 30.6, 30.3, 29.7, 28.8,
28.0, 26.7, 24.4, 23.9, 23.3, 17.8, 14.6, 13.1; HRMS calculated for
C
40H72O5N2Na 683.5329; found 683.5333.
4.2.4. N0-((4R)-4-((3R,5S,7R,10S,12S,13R,17R)-3,7,12-Trihydroxy-
10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-
yl)pentanoyl)isonicotino hydrazide (4). 62%; mp decomposes
above 150 1C; nmax/cmꢀ1 3411, 3250,3050, 2930, 2864, 1697
and 1659; dH (200 MHz, MEOD) 8.71 (d, J = 6 Hz, 2H), 8.1 (bs,
1H), 7.83 (d, J = 6 Hz, 2H), 6.9 (bs, 1H),5.49 (s, 2H), 3.97 (s, 1H),
3.8 (s, 1H), 3.2 (m, 3H), 1.1 (d, J = 5.4 Hz, 3 H), 0.92 (s, 3H), 0.73
(s, 3H); dC (125 MHz; MEOD) 173.6, 173.5, 149.3 (2C), 121.5 (2C),
72.5, 71.0, 67.7, 46.1, 45.9, 41.2, 41.0, 38.9, 38.7, 34.9, 34.8, 34.3,
34.0, 30.9, 30.0, 29.4, 27.6, 27.0, 25.9, 22.7, 21.9, 16.5, 11.8;
HRMS calculated for C30H46O5N3 528.3428; found 528.5432.
4.2.5. 4-Chloro-N0-((4R)-4-((3R,5S,7R,10S,12S,13R,17R)-3,7,12-
trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-
phenanthren-17-yl)pentanoyl)benzo hydrazide (5). 44%; mp
147–148 1C; nmax/cmꢀ1 3413, 3255, 3050, 2933, 2864, 1690
and 1660; dH (500 MHz, CDCl3 + MEOD) 7.84 (d, J = 10 Hz,
2H), 7.46 (d, J = 10 Hz, 1H), 4.51 (bs, 5H), 3.96 (s, 1H),
Acknowledgements
The authors thank CSIR, New Delhi, for financial support under
ORIGIN (CSC-0108) and OSDD (HCP-0001). SGA (31/11(802)/
2013-EMR-I) and PAP (31/11(442)/2008-EMR-I) thank CSIR,
New Delhi, for a senior research fellowship. We acknowledge
the help from Central NMR facility and centre for material
characterization division of CSIR, NCL.
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