Organogel-hydrogel transformation by simple removal or inclusion of N-Boc-protection

Article abstract of DOI:10.1002/chem.201101173

Development of organo- and hydrogelators is on the rise because of their extensive applications, from advanced materials to biomedicine. However, designing both types of gelator from a common structural scaffold is challenging, and becomes more significan

Full text of DOI:10.1002/chem.201101173

DOI: 10.1002/chem.201101173
Organogel–Hydrogel Transformation by Simple Removal or Inclusion of
N-Boc-Protection**
Tanmoy Kar, Subhra Kanti Mandal, and Prasanta Kumar Das*[a]
Abstract: Development of organo- and
hydrogelators is on the rise because of
their extensive applications, from ad-
vanced materials to biomedicine. How-
ever, designing both types of gelator
from a common structural scaffold is
challenging, and becomes more signifi-
cant if transformation between them
can be achieved by a simple method.
The present work reports the design
and synthesis of both organo- and hy-
drogelators from amino acid/peptide-
based amphiphilic precursors with a
naphthyl group at the N terminus and
a primary amine-containing hydrophilic
ethyleneoxy unit at the C terminus. In
alkaline medium, tert-butyloxycarbonyl
(Boc) protection at the primary amine
of the amphiphiles resulted in efficient
organogelators (minimum-gelation con-
centration (MGC)=0.075–1.5%w/v).
Interestingly, removal of the Boc pro-
tection from the ethyleneoxy unit,
under acidic conditions, yielded amphi-
philes capable of gelating water
(MGC=0.9–3.0%w/v). Simple protec-
tion and deprotection chemistry was
used to achieve transformation be-
tween the organogel and hydrogel by
alteration of the pH. Combinations of
different aliphatic and aromatic amino
acids were investigated to discover
their cumulative effect on the gelation
properties. Field-emission scanning
electron microscopy (FESEM) and
transmission
electron
microscopy
(TEM) were employed to investigate
the supramolecular morphology of the
thermoreversible gels. Spectroscopic in-
vestigations (FTIR, photolumines-
cence, XRD) revealed that noncova-
lent interactions, such as hydrogen
bonding, p–p stacking, and van der
Waals interactions play a decisive role
in self-assembled gelation.
Keywords: amino acids
· amphi-
philes · hydrogels · organogels ·
protecting groups
Introduction
drogen bonding, van der Waals forces, and electrostatic in-
teractions.[6,7] Despite the known influence of noncovalent
interactions in supramolecular gelation, it is difficult to ra-
tionally design and functionalize small gelator molecules for
the development of desirable materials.
The self-assembly of small functional molecules into a
supramolecular arrangement is
a prevailing approach
toward the development of soft materials.[1] Supramolecular
gels are a novel class of self-assembled materials that are re-
ceiving notable importance due to their impending applica-
tions in diverse fields, such as tissue engineering, drug deliv-
ery, template materials, enzyme-immobilization matrices,
and many more.[2–7] This ever-expanding surge has amplified
the need to design and synthesize low-molecular-weight ge-
lators (LMWGs), preferably from abundant precursors by
simple methods. Self organization of the LMWGs leads to
the formation of three dimensional (3D) higher-order ar-
rangements (e.g. fibrous, tubular) through combination of
various noncovalent interactions, such as p–p stacking, hy-
To this end, there are several reports (including ours) on
the development of amino acid/dipeptide-based LMWGs ca-
pable of immobilizing different solvents: from water to or-
ganic solvents to ionic liquids.[8–10] In spite of these libraries
of small-molecule gelators, there is still a demand for the
design of simple precursors from which a variety of gelators
can be synthesized with ease. However, reports on such
common precursors are scarce. In earlier reports, we have
shown that a hydrogen-bonding dipeptide moiety with a
long hydrophobic chain at the C terminus and a free-amine
group at the N terminus is an excellent gelator precursor.
The quaternization of this amine with methyl iodide yielded
a hydrogelator,[8a,b] and the same amine coupled with a fatty
acid resulted in an efficient organogelator.[9b] However,
transformation between these organo- and hydrogelators is
not feasible because they are prepared by different synthetic
methodology. Hence, investigation of a more simplistic ap-
proach to the development of both organo- and hydrogela-
tors from the same scaffold is a worthy challenge. Addition-
ally, transformation between an organogel and hydrogel by
simple methodology would be of great importance for wider
exploitation of these soft materials. At this point, we aim to
develop organo- and hydrogelators by incorporating a stim-
[a] T. Kar, S. K. Mandal, Dr. P. K. Das
Department of Biological Chemistry
Indian Association for the Cultivation of Science
Jadavpur
Kolkata, 700032 (India)
Fax : (+91)33-24732805
E-mail: bcpkd@iacs.res.in
[**] Boc=tert-butyloxycarbonyl.
Supporting information for this article (synthetic route to compounds
1--7 and 1a–7a; characterization data; POM image of gelator 5;
FTIR spectra of 5, 6, 5a, and 6a) is available on the WWW under
http://dx.doi.org/10.1002/chem.201101173.
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FULL PAPER
Scheme 1. Structure of amphiphiles 1–7 and 1a–7a.
Table 1. Minimum-gelation concentration (MGC) [%w/v] of 1–7 in or-
uli-sensitive functional moiety within the amino acid/dipep-
tide scaffold without compromising the hydrophilic–lipophil-
ic balance (HLB) required for gelation. Ideally, the presence
and absence of the stimuli-sensitive moiety should transform
the solvent immobilizing ability of the gelator.
Here we report the development of amino acid/peptide-
based amphiphilic gelators of both water (1a–7a) and or-
ganic solvents (1–7), synthesized from a common structural
scaffold (Scheme 1). Gelation ability was transformed be-
tween organo- and hydrogelation by the presence or ab-
sence of the well-known tert-butyloxycarbonyl (Boc) pro-
tecting group at the primary amine of the hydrophilic ethyl-
eneoxy unit at the C terminus (Scheme 2). N-Boc protection
at the primary amine under alkaline conditions resulted in
efficient organogelators (minimum-gelation concentration
(MGC)=0.075–1.5%w/v, Table 1), whereas deprotection of
the N-Boc moiety under acidic conditions yielded hydroge-
ganic solvents.[a]
Compound
Toluene
Tetralin
o-Xylene
m-Xylene
p-Xylene
1
2
3
4
5
6
7
S
S
S
1.5
0.5
0.08
0.2
S
S
S
1.5
0.55
0.08
0.25
S
S
S
S
S
S
1.5
0.45
0.08
0.25
S
S
S
1.4
0.45
0.09
0.2
1.45
0.5
0.075
0.2
[a] S=solution.
lators (MGC=0.9–3.0%w/v, Table 2). Influence of different
amino acids with aliphatic/aromatic residues on the gelation
efficiency and the corresponding changes in the supramolec-
ular arrangements of the gels was investigated by spectro-
scopic and microscopic techniques.
Scheme 2. Simple transformation between organogelators and hydrogelators.
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P. K. Das et al.
Table 2. Minimum-gelation concentration (MGC) of 1a–7a in water.[a]
comprised of two l-alanine residues, formed a stable gel in
toluene and other aromatic solvents with a MGC=1.4–
1.5%w/v (Table 1). The formation of an organogel in the
absence of any aromatic amino acid indicates the important
influence of the additional hydrogen-bonding unit of the di-
peptide in self-assembled gelation. Interestingly, the amphi-
philic compound 5, in which the N-terminal alanine residue
was replaced by l-phenylalanine, showed a three-fold en-
hancement in gelation efficiency in toluene (MGC=
0.5%w/v, Table 1) relative to 4. Improvement in the gela-
tion efficiency promoted by the synergistic effect of the pep-
tide bond and aromatic moiety provided the rationale for
the synthesis of dipeptide amphiphiles with two aromatic
residues; compound 6 (two l-phenylalanine residues) and 7
(l-phenylalanine and l-tryptophan residues). Indeed, both 6
and 7 showed a two- to six-fold improvement in gelation ef-
ficiency relative to 5 (one aromatic amino acid). Interesting-
ly, compound 6 was a super organogelator with a MGC as
low as 0.075–0.09%w/v (Table 1), which is almost 20-times
lower than the equivalent aliphatic dipeptide-based gelator
4. Thus, the concurrent presence of a hydrogen-bonding di-
peptide unit and an aromatic moiety dramatically promotes
self-aggregation of the amphiphiles, which leads to superior
gelation in organic solvents.
However, N-Boc-protected amphiphiles 1–7 did not ex-
hibit any hydrogelation ability; rather they were insoluble in
water. The Boc protection was removed (Scheme 2) by
treatment with trifluoroacetic acid (TFA) to induce more
hydrophilicity within the structures (1a–7a, Scheme 1). A
more-polar environment at the N terminus might be favora-
ble for solubilization, as well as for self-assembled gelation
in water of amphiphiles containing a free-amine group
(NH2). The gelation ability of these newly synthesized com-
pounds 1a–7a in water was studied by the “stable-to-inver-
sion of the container” method (Table 2).
Although l-alanine-containing amphiphile 1a was found
to be soluble in water, encouragingly, l-phenylalanine-based
amphiphile 2a exhibited efficient hydrogelation ability with
a MGC=1.7%w/v (Table 2). The presence of a p–p-stack-
ing unit (phenyl ring) in addition to the naphthalene moiety
seems to be important to induce hydrogelation for single
amino acid based amphiphiles. However, compound 3a,
which contained a different aromatic amino acid residue
(l-tryptophan), was found to be insoluble in water. The ex-
tended aromaticity of the indole ring in 3a might have per-
turbed the optimum HLB required for gelation. We were
keen to know the water-gelation ability of primary amine
N-Boc-deprotected hydrophilic dipeptides 4a–7a. Amphi-
phile 4a was found to be a non-gelator of water, although
its corresponding N-Boc-protected analogue 4 was an orga-
nogelator. The absence of any aromaticity within the central
dipeptide scaffold of 4a possibly enhanced its hydrophilic
character and assisted solubilization in water rather than ge-
lation. Interestingly, compound 5a, composed of a dipeptide
with one aromatic and one aliphatic amino acid, showed ex-
cellent hydrogelation ability with an MGC=0.9%w/v. This
observation reiterates the important influence of planar aro-
Compound
MGC [%w/v]
1a
2a
3a
4a
5a
6a
7a
S
1.7
I
S
0.9
3.0
I
[a] S=solution; I=insoluble.
Results and Discussion
Designing organo- and hydrogelators from a common struc-
tural scaffold instead of from a variety of structural frame-
works is of importance in the arena of soft materials. More-
over, the easier the method of transformation between these
gelators, the wider the application of such self-assembled
gels.[2–7] We wanted to develop amino acid/dipeptide-based
common precursors of gelators with appropriate stimuli-re-
sponsive functional moieties to assist subtle and simple
transformation between organo- and hydrogelation. Accord-
ingly, we synthesized a series of amphiphilic molecules from
different aliphatic and aromatic amino acids with a naphthyl
moiety at the N terminus and an ethyleneoxy unit with a
free or Boc-protected amine (NH2/NHBoc) at the C termi-
nus (Schemes 1 and 2). Amino acids were chosen as the
basic structural scaffold for the gelators because of potential
compatibility with biological systems. The ethyleneoxy unit
containing a primary amine was integrated mainly to pro-
vide the necessary hydrophilicity in the structure. The naph-
thalene unit provides a hydrophobic segment to attain the
optimum HLB, which plays a crucial role in the gelation ef-
ficiency of the compounds in solvents of different polarities.
Also, the planar naphthalene aromatic ring is expected
to facilitate self-assembled gelation through well-known
p–p-stacking interactions.[4a,11,12]
N-Boc-protected l-alanine-based amphiphile 1, with the
smallest side-chain residue, was found to be soluble in dif-
ferent organic solvents (Table 1) and insoluble in water. Sur-
prisingly, replacement of the aliphatic l-alanine residue with
an aromatic l-phenylalanine or l-tryptophan residue (com-
pounds 2 and 3, respectively) in the amphiphilic structure
failed to induce any solvent-immobilization ability, despite
additional p–p interactions of the aromatic side chain. In
this context, it is widely reported that hydrogen bonding is a
major driving force for gelation in organic solvents.[13]
Therefore, we thought that the presence of a dipeptide unit
instead of a single amino acid may influence gelation be-
cause the additional amide linkage would facilitate the hy-
drogen bonding. Thus, we synthesized dipeptide-based am-
phiphilic compounds 4–7 from combinations of aliphatic
(l-alanine) and aromatic (l-phenylalanine and l-trypto-
phan) amino acids. Encouragingly, amphiphiles 4–7 exhibit-
ed excellent organogelation efficacy in different aromatic
solvents (Table 1). Gelation ability was studied by the
“stable-to-inversion of the container” method. Compound 4,
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Organogel–Hydrogel Transformation
FULL PAPER
matic rings in gelation. However, replacement of the ali-
phatic amino acid (l-alanine) with an aromatic residue (l-
phenylalanine) resulted in a decline of the water-gelation ef-
ficiency (MGC for 6a=3.0%w/v). Following this trend, the
gelation ability was eventually lost for 7a, in which the C-
terminal l-phenylalanine residue of the dipeptide was re-
placed with l-tryptophan (a residue with an extended aro-
matic ring system). The increase in aromaticity clearly dis-
turbed the HLB due to the augmentation of the overall hy-
drophobicity of the amphiphiles.[12a] Thus, it can be inferred
that a dipeptide comprised of one aromatic and one aliphat-
ic amino acid was the ideal central scaffold for hydrogela-
tion of amphiphiles that contained a primary amine group.
Interestingly, hydrogelators 1a–7a reverted to efficient orga-
nogelators 1–7 by N-Boc protection in alkaline medium
(Scheme 2). In summary, transformation between organo-
and hydrogelation ability from a common structural scaffold
was achieved by simple pH-responsive removal or inclusion
of a Boc moiety.
Figure 1. Variation of Tgel with gelator concentration.
All of the hydro- and organogels were thermoreversible
in nature; they melted upon slow heating and returned to
gel form upon cooling. The gel-melting temperature (Tgel) is
the temperature at which the gel-to-sol transition occurs.
The Tgel values of the gelators were comparable at their
MGCs (37–428C) and increased with increasing gelator con-
centration (Figure 1).[14] All of the gels were stable at room
temperature for several months.
fiber. This reiterates the pronounced effect of an aromatic
residue in modulating the gelation efficacy. In the case of
the dried gel of 6 (two aromatic l-phenylalanine residues), a
considerable change in the nature of the fiber was observed.
The network was formed by intertwined fibrils approximate-
ly 40–50 nm thick. The length of the fibers was found to be
several micrometers, with uniform diameter (Figure 2c).
Presumably, the molecular structure played an important
role in the determination of the morphology of the network.
This densely packed, intertwined fibrous network entraps
more solvent molecules within its supramolecular assembly
and is the most efficient organogel (MGC=0.08%w/v,
Table 1) among all the gelators as a result. The supramolec-
ular arrangement of gelator 7 (an l-phenylalanine and l-
tryptophan dipeptide core) also showed an entangled net-
work of fibrils with a thickness of approximately 50–60 nm.
Some of the fibers were curled together to form thicker
fibers of approximately 150–200 nm diameter (Figure 2d).
Microscopic studies: Field-emission scanning electron mi-
croscopy (FESEM) was employed to gain visual insight into
the supramolecular arrangement of both the hydro- and or-
ganogels. All the xerogels, prepared either from water or
toluene, showed the presence of a 3D fibrillar network at
their MGC (Figure 2), although the nature and size of the
fiber was dissimilar and dependent on the structure of the
LMWG. The xerogel of 4 (comprised of two aliphatic amino
acid residues) showed fibrous morphology with an average
fiber thickness of 350–400 nm and fiber length up to several
micrometers (Figure 2a). The
xerogel of 5 (one aliphatic and
one aromatic residue) pre-
pared from toluene showed an
interconnected fibrillar net-
work with an individual fiber
diameter of approximately
120–150 nm. Some of the
fibers were associated with
each other to form thicker
fibers of approximately 250 nm
diameter (Figure 2b). Upon in-
corporation of an l-phenylala-
nine residue in the gelator
structure,
a
three-fold im-
provement in gelation efficien-
cy was observed for 5, relative
to 4, attributed to this varia-
tion in nature and size of the
Figure 2. FESEM images of dried samples of a) 4, b) 5, c) 6, and d) 7 in toluene; FESEM images of dried sam-
ples of e) 5a and f) 6a in water at the MGC.
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P. K. Das et al.
Similar entangled fibril networks were observed for the
hydrogels. In the case of 5a, densely populated, intercon-
nected fibrils with uniform thickness (ꢀ40–50 nm) (Fig-
ure 2e) notably improved the water-immobilization ability
in the self-assembled state. The hydrogel of 6a showed the
presence of lamellar, as well as intertwined fibril structure
of comparable diameter but with a length of a few microme-
ters (Figure 2 f). The similarity in the fibril network of both
the organo- and hydrogels indicates that transformation be-
tween the gelators does not affect the supramolecular ar-
rangement in self-assembled gelation. This could be due to
the common structural scaffold for both the organo- and hy-
drogelators, the only difference is the presence or absence
of a Boc moiety. Hence, simply by pH-sensitive removal or
inclusion of a protecting group, a switch in the gelation be-
havior to extreme opposite polarity solvents can be easily
achieved without compromising the self-aggregation behav-
ior of the amphiphiles.
The presence of fibrous morphology within the organogel
of 6 (the best organogelator) and hydrogels of 5a and 6a
was further confirmed by transmission electron microscopy
(TEM) images of their respective xerogels (Figure 3). The
TEM images at five-times lower concentration than the
MGC showed similar intertwined fibers of approximately
30–40 nm thickness for 6 (Figure 3a), and 5a and 6a exhibit-
ed fibers of several micrometers in length and approximate-
ly 40 nm diameter (Figure 3b,c), which supports the corre-
sponding FESEM images (Figure 2e,f). A birefringence
character (Figure S1 in the Supporting Information) within
the entangled fibrous network was also observed in the po-
larizing optical microscopic (POM) image of 5 (xerogel pre-
pared from toluene). The observed birefringence in the
POM image indicates the high degree of molecular ordering
in the gel state.[15]
tra is analogous to that generally observed for the b-sheet
(but not by the position of the peaks) protein structure (pos-
itive peak at 197 nm and negative peak at 218 nm).[17] More-
over, the sharp increase in the molar ellipticity with increas-
ing gelator concentration also suggested a highly ordered ar-
rangement of chiral planes at the supramolecular level.
FTIR study: Participation of noncovalent interactions, such
as hydrogen bonding, during the self-assembly of the gela-
tors was studied by FTIR spectroscopy. FTIR spectra were
recorded for toluene xerogels, D2O gels, and the non-self-as-
sembled state of the gelators in chloroform. The FTIR spec-
tra of gelators 5, 6, 5a, and 6a in chloroform showed trans-
mission bands at v˜ =3415–3420, 1665–1671, and 1512–
1525 cmÀ1, which are characteristic of non-hydrogen-bonded
À
À
N H (amide A), C=O (amide I), and N H (amide II) fre-
quencies, respectively (Figure 5, Figure S2 in the Supporting
Information).[13c,14a,18] However, the transmission bands of
the corresponding toluene xerogels of 5 and 6 appeared at
n˜ =3280, 1639–1642, and 1542–1545 cmÀ1, respectively (Fig-
ure 5a, Figure S2a in the Supporting Information). This low-
À
ering of the stretching bands for N H (amide A) and C=O
À
(amide I), and increase in the bending band for N H (ami-
de II) indicates the presence of intermolecular hydrogen
bonding between the carbonyl group and amide NH group
in the gel state.[14a,18] Existence of intermolecular hydrogen
bonding was also observed for 5a and 6a; the C=O
(amide I) band at n˜ =1668 cmÀ1 in chloroform shifted to
n˜ =1627 and 1631 cmÀ1, respectively, in the gel state in D2O
(Figure 5b, Figure S2B in the Supporting Information).
Thus, intermolecular hydrogen bonding plays an important
role in the self-assembled gelation of both organo- and hy-
drogelators.
Luminescence study: In addition to hydrogen bonding, hy-
drophobic interactions are also known to play a crucial role
in supramolecular gelation. To understand the participation
of hydrophobic interactions during gelation, we examined
the intrinsic fluorescence of the aromatic rings of the gela-
tors rather than utilizing an external fluorescence probe.
The luminescence spectra of gelators 6 (Figure 6a) and 5a
(Figure 6b) were recorded with varying concentrations in
toluene and water, respectively, upon excitation of the mole-
cules at 280 nm. Initially, at very low concentration, the
emission intensity at 340 nm with a shoulder at 330 nm was
found to gradually increase with concentration up to
0.01%w/v, which is far below
Circular dichroism (CD) study: The expression of supra-
molecular chirality that originates from the highly ordered
arrangement of hydrogelators 2a, 5a, and 6a was investigat-
ed by recording their CD spectra in water at different con-
centrations (Figure 4).[16] The aqueous solutions of all of the
hydrogelators had a negative peak at 228–233 nm and a pos-
itive peak at 218 nm in the spectra. The observed Cotton
effect at the amide absorption region (228–233 nm) is due to
the p–p* transition of the amide bond. These transitions are
extremely sensitive to coupling with neighboring amide
groups.[16b,c] In all cases, the pattern of the peaks in the spec-
the MGC for both gelators.
However, with further increase
in the gelator concentration a
sharp decrease in emission in-
tensity was observed, along
with broadening of the emis-
sion peak up to the MGC and
above. The emission intensity
increased until the gelators
Figure 3. TEM images of dried samples of a) 6 (in toluene), b) 5a, and c) 6a (in water).
were in a non-self-assembled
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Organogel–Hydrogel Transformation
FULL PAPER
Figure 5. a) FTIR spectra of the xerogel of 6 in toluene (c) and in
chloroform (g). b) FTIR spectra of 5a in D2O in the gel state (c)
and in chloroform (g).
both the organogels and hydrogels to investigate the molec-
ular packing and orientation of the gelators in the supra-
molecular gel state. Xerogels of 5 and 6 (taken as represen-
tative) obtained from toluene gave a peak at 2q=19.408
(d spacing=4.57 ꢁ), accompanied by another peak at 2q=
9.68 with a d spacing of 9.4 ꢁ (Figure 7a). These two peaks
usually indicate the presence of antiparallel ordering, in
which each molecule aligns (via cross) with two other mole-
cules and forms hydrogen bonds.[4a] Similarly, hydrogel 2a
showed peaks at 2q=9.5 and 18.38 (d spacing=9.6 and
4.33 ꢁ, respectively) and hydrogel 5a showed peaks at 2q=
10.6 and 20.938 (d spacing=8.34 and 4.23 ꢁ, respectively;
Figure 7b). This periodicity arises from spacing between the
peptide chains and two stacked layers. Another peak at 2q=
23.78 (d spacing=3.75 ꢁ) further indicates the presence of
the p–p-stacking interaction between the planar aromatic
rings in the self-assembled structure.[20] These aromatic–aro-
matic interactions not only facilitate the long-range ordering
of the molecules but also provide the hydrophobic environ-
ment that greatly increases the propensity for self-assembled
gelation. The observed spectroscopic and microscopic stud-
ies suggest the involvement of hydrogen bonding, p–p stack-
Figure 4. CD spectra of a) 2a, b) 5a, and c) 6a, with varying concentra-
tions [%w/v] in water at RT.
state. At higher concentrations (>0.01%w/v), the amphi-
philic molecules began to self-assemble for gelation. In this
process of self-organization, the planar aromatic rings got
closer to each other, which gradually quenched the fluores-
cence ability of the naphthalene unit, as well as the phenyl
rings of the amino acid residues.[19]
XRD study: In addition to the preceding microscopic and
spectroscopic studies, we measured the XRD spectra of
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P. K. Das et al.
Figure 6. a) Luminescence spectra of gelator 6 at varying concentrations
in toluene at RT. lex =280 nm; [6]: a=0.0025, b=0.005, c=0.0075, d=
0.01, e=0.025, f=0.05, g=0.075, h=0.1, i=0.2, j=0.3%w/v. b) Lumines-
cence spectra of gelator 5a at varying concentrations in water at RT.
lex =280 nm; [5a]: a=0.0025, b=0.005, c=0.01, d=0.025, e=0.05, f=
0.075, g=0.1, h=0.5, i=1.5%w/v.
Figure 7. XRD spectra of a) dried organogels of 5 and 6; b) dried hydro-
gels of 2a and 5a.
stress value at which G’’ becomes higher than G’ (stress-am-
plitude sweep experiment).[21] We carried out rheological ex-
periments with the organogels of 5 and 6 and hydrogel 5a.
Initially, for all of the gels, G’ was higher than G’’ and with a
gradual increase in applied stress both G’ and G’’ remained
invariant, but deviated from linearity beyond a certain stress
(Figure 9). In the case of the organogel of 5, yield stress at
the crossover point was 27.2 Pa (Figure 9a), whereas for 6
yield stress was higher than 100 Pa (Figure 9b). This implies
superior mechanical strength of the organogel of 6 relative
to that of 5, which is in agreement with the better gelation
efficiency of 6. This considerable difference in the viscoelas-
tic properties of the organogels can be attributed to the var-
iation in the size and dimension of fibers within the inter-
twined supramolecular 3D network of the gels.[21b] However,
the yield stress for hydrogel 5a was found to be much lower
(9.5 Pa) than that of either of the organogels studied (Fig-
ure 9c). The organogelator 5 and hydrogelator 5a are com-
prised of a common structural motif, distinguished by the
presence or absence of an N-Boc moiety. This subtle varia-
ing, and hydrophobic interactions in the self-assembled gela-
tion through an ordered arrangement of the amphiphiles.
This is schematically shown in Figure 8 for representative
gelator, 6.
Rheology: The mechanical strengths of representative
organo- and hydrogels were characterized by rheological ex-
periments. Rheological studies give an indication of the flow
behavior and rigidity of the gel. The two main parameters
are the storage modulus (G’), which represents the ability of
the deformed material to store energy, and the loss modulus
(G’’), which corresponds to the flow behavior of the materi-
al under stress. In the gel state G’>G’’ (G’ and G’’ꢀw0) and
in the sol state G’’>G’ (G’ꢀw2 and G’’ꢀw; w=angular fre-
quency). The crossover point between G’ and G’’ (known as
yield stress) indicates the transition point from elastic solid
to viscous liquid. This is determined by measurement of the
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Chem. Eur. J. 2011, 17, 14952 – 14961

Organogel–Hydrogel Transformation
FULL PAPER
(HOBT), and solvents were pur-
chased from SRL, India. Trifluoroace-
tic acid (TFA), a-naphthyl acetic
acid, 1,1ꢂ-carbonyl diimidazole (CDI),
thionyl chloride, and sodium hydrox-
ide were procured from Spectrochem,
India. All deuterated solvents for
NMR and FTIR spectroscopy studies
and
2,2ꢂ-(ethylenedioxy)bis(ethyla-
mine) were obtained from Aldrich
Chemical Co. TLC was performed on
Merck precoated silica gel 60-F254
plates. 1H NMR spectra were record-
ed on an AVANCE 500 MHz
(Bruker) spectrometer. Mass spectra
were acquired by electron-spray ioni-
zation (ESI) on
a Q-TOF-micro
quadrupole mass spectrometer (Mi-
cromass). Elemental analyses were
performed on Perkin–Elmer 2400
CHN analyzer.
Synthetic procedure: All amphiphilic
gelators were synthesized by well-es-
tablished peptide chemistry (see the
Supporting Information, Scheme S1).
Synthesis of 1–3: The carboxylic acid
group of the l-amino acid was pro-
Figure 8. Schematic representation of the possible arrangement of 6 in the gel state.
tected by conversion to
a methyl
ester. The ester-protected amino acid
was coupled with a-naphthyl acetic
acid in dry CH2Cl2 with CDI (1 equiv) as the coupling agent. The ester-
protected amide was purified by column chromatography on 60–120
mesh silica gel (ethyl acetate/hexane). The product was then hydrolyzed
by treatment with 1n NaOH solution (1.1 equiv) in MeOH for 6 h with
stirring at RT. The reaction mixture was concentrated on a rotary evapo-
rator, then diluted with water. The aqueous mixture was washed with
ether, subsequently acidified with a 1n aqueous solution of HCl, and the
carboxylic acid was extracted into ethyl acetate. This acid was coupled
with mono-Boc-protected 2,2ꢂ-(ethylenedioxy)bis(ethylamine) by treat-
ment with DCC (1 equiv), DMAP (cat.), and HOBt (1 equiv) in dry
CH2Cl2. The product was purified by column chromatography on 100–
200 mesh silica gel (methanol/chloroform).
tion in their structure provides an additional hydrogen-
bonding site for organogel 5 due to the extra amide linkage,
which might be the possible cause for its higher elasticity
relative to hydrogel 5a.[21b] The observed rheological behav-
ior of the gels is in accordance with the viscoelastic behavior
of soft materials reported in literature.[21]
Conclusion
We have successfully demonstrated an easy approach to de-
velop efficient organo- and hydrogelators from a common
amino acid/dipeptide-based precursor scaffold. Transforma-
tion was possible by simple pH-responsive inclusion or re-
moval of an N-Boc moiety. A detailed structure–property
investigation was carried out by judicious alterations of the
amino acid residues to determine a rationale behind the de-
velopment of efficient gelators. Involvement of different
noncovalent interactions in the self-assembled gelation was
established by spectroscopic and microscopic techniques.
The supramolecular assembly of these amphiphiles could be
utilized for the development of soft nanocomposites by in
situ synthesis of metal nanoparticles within the gel matrix.
Further, these gel-nanoparticle soft composites have poten-
tial applications in diverse fields, from materials science to
biotechnology.
Synthesis of compounds 4–7: For the synthesis of amphiphiles 4--7, the
methyl ester of the appropriate l-amino acid was coupled with a-naph-
thyl acetic acid, then hydrolysis by treatment with NaOH gave the de-
sired carboxylic acid, as described above. This acid was further coupled
with a second methyl ester-protected amino acid by reaction with DCC
(1 equiv), DMAP (cat.), and HOBt (1 equiv) in dry CH2Cl2. This methyl
ester was hydrolyzed with NaOH, as described above, to afford the acid.
The free acid at the C terminus of the dipeptide was coupled with mono-
Boc-protected 2,2ꢂ-(ethylenedioxy)bis(ethylamine) by treatment with
DCC (1 equiv), DMAP (cat.), and HOBt (1 equiv) in dry CH2Cl2. The
product was purified by column chromatography on 100–200 mesh silica
gel (methanol/chloroform).
Synthesis of compounds 1a–7a: The pure N-Boc-protected compounds
1–7 were Boc-deprotected by treatment with TFA (2 equiv) in dry
CH2Cl2 under magnetic stirring for approximately 2 h. The volatile com-
pounds were removed on a rotary evaporator and CH2Cl2 was added.
The CH2Cl2 layer was washed with a 10% aqueous solution of Na2CO3
and then brine, to neutrality. The organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure to give the desired
amine. The product was purified by column chromatography on 100–200
mesh silica gel (methanol/chloroform). All compounds were character-
ized by NMR spectroscopy, elemental analysis, and mass spectrometry;
the data are provided in the Supporting Information.
Experimental Section
Preparation of gels: The required amount of compound was added to a
screw-capped vial with an internal diameter (i.d.) of 10 mm, then slowly
heated to dissolve, either in organic solvent or water. The solution was al-
Materials: All amino acids, Boc anhydride, dicyclohexylcarbodiimide
(DCC), 4-N,N-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole
Chem. Eur. J. 2011, 17, 14952 – 14961
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14959

P. K. Das et al.
ing the temperature at a rate of 28C/min. The Tgel was defined as the
temperature (Æ0.58C) at which the gel melted and started to flow.
Microscopic study: FESEM images were obtained on a JEOL-6700F mi-
croscope. A drop of gel (at the MGC) was placed on a cover slip and
dried for few hours under vacuum before imaging. TEM experiments
were performed on a JEOL JEM 2010 high-resolution microscope oper-
ated at an accelerating voltage 200 kV. Dilute solutions of gel were
placed on a 300-mesh carbon-coated Cu grid and dried for few hours
under vacuum before imaging. The hydrogelators were negatively stained
with uranyl acetate (2%w/v). POM images were taken on Olympus
U-TV1X-2 microscope.
FTIR measurements: FTIR measurements of the gelators in CHCl3 solu-
tion (KBr cell), D2O (CaF2 cell; for hydrogels), and dried gels from tolu-
ene (KBr pellets) were performed on a Perkin–Elmer Spectrum 100
FTIR spectrometer.
Circular dichroism (CD) spectra: CD spectra of aqueous solutions of ge-
lators 2a, 5a, and 6a with varying concentrations were recorded in a
quartz cuvette (1 mm path length) on a JASCO J-815 spectrometer.
XRD spectra: XRD measurements of the xerogels were obtained on a
Bruker D8 Advance diffractometer fitted with a CuKa radiation source
(a=0.15406 nm) with a voltage and current of 40 kV and 30 mA, respec-
tively. All xerogels were scanned from 1 to 408.
Fluorescence spectroscopy: The emission spectra of the amphiphiles
were recorded on a Varian Cary Eclipse luminescence spectrometer at
varying concentration from 0.0025%w/v–>MGC. A stock solution of
the amphiphiles was prepared, which was subsequently diluted in water
or toluene to obtain the spectra. Solutions were excited at lex =280 nm.
The excitation and emission slit width were both 5 nm.
Rheological experiments: The rheological experiments were performed
by cone-and-plate geometry (diameter was 40 mm) on the rheometer
plate with an Advanced Rheometer AR 2000 (TA Instruments, USA).
The organogels of 5 and 6 and hydrogel of 5a were prepared at 2%w/v
and kept overnight at RT. The gel was scooped on the rheometer plate
so that there was no air gap with the cone. Stress-amplitude sweep ex-
periments were performed at a constant oscillation frequency of 1 Hz for
the strain range 0.01–100 Pa at 258C and the storage modulus (G’) and
the loss modulus (G’’) were plotted against oscillatory stress.
Acknowledgements
P.K.D. is thankful to Department of Science and Technology, India for fi-
nancial assistance. T.K. and S.K.M. acknowledge the Council of Scientific
and Industrial Research, India for Research Fellowships.
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Received: April 16, 2011
Published online: November 22, 2011
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www.chemeurj.org
14961