Salt complexes of two-component N-acylamino acid diastereoisomers: Self-assembly studies and modulation of gelation abilities

Article abstract of DOI:10.1016/j.tetlet.2012.09.107

The self-assemblies and gelation of various organic solvents by salt complexes of two-component N-acylamino acid diastereoisomers are described. The potent organogelator, N-(2-aminoethyl)-α-[-(1-oxoheptadecyl)amino]phenyl) propanamide, was mixed with various N-acyl leucines having different fatty alkyl chain lengths at a ratio of 1:1. In some cases, their complexation resulted in modulations of the current gelation abilities. When the l-form of the organogelator was used for mixing, the gelation ability appeared to be independent of the hydrophobic nature of the N-acyl leucine. This is not observed when the racemate form of the organogelator was used. Moreover, a minimum gelation concentration (MGC) in aromatic solvents as well as improvements of the gelation ability such as formation of a robust hydrogel in water, gelation of the R-propylene carbonate, and unexpected gelation of pyridine were observed. The supramolecular gels were analyzed by Fourier Transform-Infrared (FT-IR), ¹H nuclear magnetic resonance (NMR) spectroscopies, and rheology analysis. The phase transition temperatures (T _g-s) were determined using differential scanning calorimetry (DSC). Homogeneity of the gel networks was observed by field emission scanning microscopy (FE-SEM) and transmission electron microscopy (TEM). The lamella structure was confirmed by X-ray diffraction (XRD).

Full text of DOI:10.1016/j.tetlet.2012.09.107

Tetrahedron Letters 53 (2012) 6588–6593
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Salt complexes of two-component N-acylamino acid diastereoisomers:
self-assembly studies and modulation of gelation abilities
⇑
Frederic Delbecq, Yuki Masuda, Yuki Ogue, Takeshi Kawai
Department of Industrial Chemistry, Tokyo University of Science 1-3 Kagurazaka, Shinjuku, Tokyo 162-8614, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The self-assemblies and gelation of various organic solvents by salt complexes of two-component N-acyl-
Received 7 August 2012
Revised 20 September 2012
Accepted 24 September 2012
Available online 29 September 2012
amino acid diastereoisomers are described. The potent organogelator, N-(2-aminoethyl)-a-[-(1-oxohep-
tadecyl)amino]phenyl) propanamide, was mixed with various N-acyl leucines having different fatty alkyl
chain lengths at a ratio of 1:1. In some cases, their complexation resulted in modulations of the current
gelation abilities. When the L-form of the organogelator was used for mixing, the gelation ability
appeared to be independent of the hydrophobic nature of the N-acyl leucine. This is not observed when
the racemate form of the organogelator was used. Moreover, a minimum gelation concentration (MGC) in
aromatic solvents as well as improvements of the gelation ability such as formation of a robust hydrogel
in water, gelation of the R-propylene carbonate, and unexpected gelation of pyridine were observed. The
supramolecular gels were analyzed by Fourier Transform-Infrared (FT-IR), 1H nuclear magnetic resonance
(NMR) spectroscopies, and rheology analysis. The phase transition temperatures (Tg–s) were determined
using differential scanning calorimetry (DSC). Homogeneity of the gel networks was observed by field
emission scanning microscopy (FE-SEM) and transmission electron microscopy (TEM). The lamella struc-
ture was confirmed by X-ray diffraction (XRD).
Keywords:
N-acyl amino acids
Salt complexes of N-acylamino acid
diastereoisomers
Gelation modulation
Self-assembly
Ó 2012 Elsevier Ltd. All rights reserved.
Introduction
tem employing a mixture of lysine derivatives and simple fatty
acids. This system imparts gelation abilities in oils and hydrocar-
Supramolecular gels obtained by self-assembly of low molecu-
lar weight organogelators (LMOGs) have received considerable
attention as biodegradable and biocompatible soft materials. The
gels are not only used in drug delivery systems (DDS),1,2 cosmetic
materials, separation and biomimetics agents,3–6 but also as tem-
plates for inorganic material syntheses.7–10
bons, whichby themselves do not exhibit organogelation properties.
They can act effectively as an organogelator by forming a two-com-
ponent salt species. Despite the ionic character of the resulted salt
species, no hydrogelation phenomenon was reported for this work.
Tuning of the current gelation power and nature of existing
LMOGs should be possible by the two-component approach. Based
on the resolution of racemic amines via a simple acid–base interac-
tion with a commercial N-acetyl leucine23 as the chiral resolving
agent, we evaluated the effect of stereochemistry on the gelation
ability using various diastereoisomeric and ionic species. In this
study, we investigated the possibility of gelation ability modula-
tion for potent organogelators 1 and 2 by adding equimolar
amounts of acidic and optically active N-acyl leucines 3a–d
(Fig. 1). Both organogelators 1 and 2 showed gelation ability, but
the effect of the N-acyl leucines added remains unclear. In an at-
tempt to minimize the toxicity of the organogelators, we focused
only on the fatty acid grafted on the amino acid residue.
During the gelation procedure, one dimensional fiber growth is
effectively promoted in the solvent by directional intermolecular
interactions (such as H-bonding,
packing).
p–p stacking, and lateral chain
The LMOG finally self-assembles into a three dimensional fibril-
lar network incorporating the solvent molecules into the intersti-
tial space. In the literature, various compounds with long
hydrophobic alkyl tails grafted on hydrophilic heads, such as sac-
charides,11–16 amides of peptides,17 and amino acids,18–20 ureas,21
steroid derivatives, and multi-component systems have been re-
ported. However, it is still difficult to predict gelation based on
the molecular structures of gelator candidates. In fact, most gela-
tors have been discovered by chance rather than by design.
Besides developing synthetic strategies, another approach to
realize new gelators is to develop a two-component system. Re-
cently, Suzuki et al.22 developed an alternative two-component sys-
Results and discussions
Formation and characterization of supramolecular gels
The typical gelation procedure involved 1–10 mg of organogela-
tors 1 or 2 with and without one equimolar of 3a, b, c, or d in
1.0 ml of solvent. The solution was heated until the material was
⇑
Corresponding author. Tel.: +81 3 5228 8312; fax: +81 3 5261 4631.
E-mail address: kawai@ci.kagu.tus.ac.jp (T. Kawai).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.107

F. Delbecq et al. / Tetrahedron Letters 53 (2012) 6588–6593
6589
The results indicate that the 1+3d system has the highest gelation
ability and the 1+3b system has the lowest gelation ability. In the
case of 3b, the compound does not seem to be lipophilic enough
even though it is not really soluble in water.
The same experiment was conducted for organogelator 2 and
the results are shown in Table 2.
O
H
N
N
H
NH2
O
1 : L-Form
2 : D,L-Form
There are some slight differences between the gelation abilities
of organogelators 1 and 2 with or without 3a–d. One of the major
differences was the decrease in gelation ability when 3a was added
to 2, due to the presence of the salified form of 1+3a which is also
not soluble at room temperature causing this present salified
material to precipitate in the solvent. For the mixture with 3a, no
gelation phenomenon was observed in methanol and acetonitrile.
However, gelation ability inferior to what we obtained with the
simple 1+3a two-component system was observed in chloroform
at a 0.7 wt % concentration. In hexane and aromatic solvents, the
physico-chemical behaviors of the 2+3a–d systems are different
from those of the 1+3a system, for example, the most regular
MGC increase in function of the fatty alkyl chain elongation. In Fig-
ure 4b, the calculated gelation numbers of the 2+3a–d systems
confirm that the racemate nature of 2 controls the variation of
the gelation ability in each case independent of the lipophilic nat-
ure of 3a–d, particularly with 3b. Surprisingly, when one equiva-
lent of 3d was added to 2 at a ratio of 1:1 in pyridine (1 wt %
concentration), a transparent gel was formed.
O
OH
CH3(CH2)n
N
H
O
3a : n=0 ; 3b : n=4 ; 3c : n= 10 ; 3d : n=14
Figure 1. Structure of organogelators 1 and 2 as well as N-acyl leucines 3a–d.
completely dissolved, followed by ultrasound treatment. The
transparent or turbid solution was then kept at a temperature close
to 25 °C forming a gel quickly. The gelation properties and MGC of
1 and the two-component systems are listed in Table 1.
Organogelator 1 was a potent organogelator in various organic
solvents such as acetonitrile or 1-octanol at a concentration range
of 0.1–1 wt %; however, it did not exhibit gelation ability in water.
Organogelator 1 was able to gelate hydrophobic solvents such as
toluene, hexane, or chlorobenzene (at concentrations of 0.1, 0.4,
and 0.5 wt %, respectively), but it had high solubility in chloroform
and methanol at room temperature. In addition, a robust gel was
obtained in acetonitrile. In each case, gelation was observed at
low concentrations below 1 wt %. The salt complex 1+3a formed
when 1 was mixed with 3a, and the gelation ability of 1 was im-
FE-SEM and TEM observation of the xerogels
FE-SEM images of air-dried self-assembled xerogels obtained
from various solvents; containing the organogelator 1 with 3a or
3d are shown in Figure 2. In these images the network consists
of long thinner fibers with diameters of 1 lm. Figure 4a shows dif-
proved. When the D-form of 3a was employed instead of the L-
ferences in morphology for each sample of the vacuum-dried
organogels obtained in toluene and similar morphologies for the
air-dried gels obtained in chlorobenzene and hexane. We consider
that a correlation exists between the irregular MGC measured in
the aromatic or apolar solvents and the network morphologies.
In the presence of 3a–c, a folded network structure was obtained
rather than the expected fibrillar network structure. Upon forming
a salt complex with 3d, the fibrillar network was recovered. Cer-
tainly, the elongation of the alkyl chain grafted on the leucine res-
idue must be considered. A second intermolecular lipophilic
interaction promoted by the long alkyl chain of 3d could be the
reason for stronger stabilization of the bilayer, due to an increase
of the global lipophilicity of the complex salt formed.
form, no variation of the gelation abilities was observed (result
not shown here), except for gelation of the chiral R-propylene car-
bonate at a 1 wt % concentration. Despite a small increase of the
MGC in the aromatic solvent and hexane, the addition of 3a pro-
moted good gelation ability in water and CHCl3 at concentrations
of 0.7 and 0.8 wt %, respectively. The addition of 3b also conferred
gelation ability to organogelator 1 in pure water, forming an opa-
que gel at room temperature, but the gelation capacity decreased
in CHCl3, acetonitrile, and methanol, and was not observed for 3c
and 3d. On the other hand, the gelation number18 was calculated
for each 1+3a–d system (Fig. 4b) in aromatic solvents and hexane.
Table 1
Gelation properties and MGC of 1 and the 1+3a–d two-component systems in water
and various solvents
Table 2
Gelation properties and MGC of 2 and the corresponding 2+3a–d two-component
systems in water and organic solvents
Solvent
1
1+3a
1+3b
1+3c
1+3d
Toluene
Water
MeOH
Acetonitrile
CHCl3
ClC6H5
TGa
I
S
TGd
TGf
S
OG
TG
TGb
PG
TGh
TGg
OGd
S
PG
S
TG
S
TG
TGf
I
S
TGb
I
Solvent
2
2+3a
2+3b
2+3c
2+3d
PG
PG
TG
TGb
PG
PG
Toluene
Water
MeOH
Acetonitrile
CHCl3
ClC6H5
TGa
I
TGd
P
S
TGf
OGd
S
PG
S
TG
S
TG
TGd
P
S
TGc
I
OG
S
PG
S
OGf
OGa
S
PG
PG
PG
TGb
TG
OGc
TGd
S
TGe
S
P
PG
S
Pyridine
Hexane
TGe
TGf
S
TGc
TGg
TGa
S
TGc
S
Pyridine
Hexane
TGa
TGf
TGd
TG: transparent gel at 27 °C; OG: opaque gel; S: soluble at room temperature; PG:
partial gel (gelatinous precipitate); I: insoluble material.
MGC:
TG: transparent gel obtained at 27 °C; OG: opaque gel; S: soluble at 25 °C; PG:
partial gel (gelatinous precipitate); I: insoluble material.
MGC:
a
0.1 wt %.
0.3 wt %.
0.4 wt %.
0.5 wt %.
0.6 wt %.
0.7 wt %.
0.8 wt %.
b
c
a
0.2 wt %.
0.3 wt %.
0.5 wt %.
0.6 wt %.
0.7 wt %.
0.9 wt %.
d
b
e
c
f
d
g
e
h
f
0.9 wt %.

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F. Delbecq et al. / Tetrahedron Letters 53 (2012) 6588–6593
Figure 2. SEM images of the xerogels in CHCl3 containing (a) 1+3a and (b) hydrogel 1+3a, (c) in R-propylene carbonate containing 1+3a (D-form) and (d) in pyridine
containing 2+3d.
TEM images of non denatured toluene organogels are shown in
Figure 3. For 1 and 1+3a, the photographs show fibrils of several
nanometers in length and approximatively 20 nm in thickness
forming an entangled network. Only in the case of 1+3d, large
structures with 100 mm in thickness were found, the same tubular
structure were also observed by SEM microscopy (Fig. 4a). All re-
sults indicate clearly the contribution of the additive 3a–d in a
more and complicated gel network.
plete suppression of the signals, for the two-component systems,
only the characteristic signals of the phenyl group and those of
the methyl group of 3a were apparent. The spectra in all cases were
similar, as no p–p stacking between the aromatic moieties was ob-
served in the experiment; the phenyl groups were not involved in
the stabilization of the fibrillar network, especially in presence of
an additive. The optical nature of
L or D-form of 3a did not play
an important role in the network structure.
The FT-IR spectra of the xerogel samples derived from their cor-
responding vacuum-dried organogels 1+3a–d (L-form) were mea-
1H NMR and IR spectroscopy
sured. For 1, the absorption bands specific to the trans alkyl
Since organogel 1 with and without 3a as well as its
D
-form gave
chain appeared at 2917 and 2849.6 cmꢀ1. In the presence of an
robust gels in toluene, 1H NMR spectra were measured at 25 °C in
toluene-d8. In the gel state, except for 1 itself showing the com-
equivalent amount of the
L- or D-form of 3a, one of these absorption
bands reached 2915 and 2917 cmꢀ1, proving that the alkyl chain
Figure 3. TEM images of (a) 1, (b) 1+3a, and (c) 1+3d gels (1 wt %) in toluene.

F. Delbecq et al. / Tetrahedron Letters 53 (2012) 6588–6593
6591
Figure 4. (a) SEM images of air-dried xerogels in toluene containing the 1+3a–d systems. (b) Bar diagram displaying gelation numbers of the 1+3a–d and 2+3a–d systems in
toluene, chlorobenzene, and hexane.
packing reinforce the structure particularly for the 1+3a (
system. Similar absorption bands were observed with the other
xerogels 1+3b–d.
FT-IR analysis of 1 dissolved in CD3OD revealed that the amide
bands appeared at 3428 (NH); 1690 cmꢀ1 (amide I-Fig. 5) and
1500 cmꢀ1 (amide II) which is representative of a non H-bonded
amide group. In the case of 1+3a and 1+3d in solution, the bands
of NH and amide I were also found at 3347; 1654 cmꢀ1 and
3355; 1666 cmꢀ1 respectively.
D
-form)
bands in the FT-IR spectra for all xerogels 1+3a–d appeared around
1635 cmꢀ1 and no signal was observed at 1690 cmꢀ1. Thus, we can
confirm that despite the presence of 3a–d, the fibrillar network
consists of parallel b-sheets participating in stronger intermolecu-
lar hydrogen bonding due to consecutive amide bonds.
For 1, the wavenumber of amide II did not change drastically
(from 1539 cmꢀ1 to 1538 cmꢀ1) even when mixed with 3a, 3b,
3c, or 3d. In the equimolar mixture, the –COOH vibration band of
3a at 1700 cmꢀ1 was replaced by the new –COO– band at
1402 cmꢀ1 (Fig. 5), proving that the formed salt did not disturb
the stability of the gel network. Accordingly, we consider that
In the gel state, the characteristic bands of NH and amide I were
observed at 3290 and 1635 cmꢀ1 for organogelator 1. The amide I
Figure 5. FT-IR spectra. On left: NH band variations for 1 and 3a in solution and in the gel state. On right: Suppression of the leucine COOH absorption band of 3a in a gelated
toluene sample.

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F. Delbecq et al. / Tetrahedron Letters 53 (2012) 6588–6593
Table 3
1.10 nm (1:1/2:1/3:1/4) for 1 and 3.80, 2.02, and 1.44 nm (1:1/2:1/
Gel melting temperature from DSC measurement
3) for 2 were obtained. The d-spacing ratios are in the ratio of re-
ciprocal in integers characteristic of the lamellar structure. More-
over, in the wide angle region, the xerogel showed sharp
diffraction peaks. In fact, the bilayer thickness was 2 times smaller
at full extension, indicating a lamella network structure and also a
highly ordered lateral chain packing.
1
1+3a
1+3c
1+3d
Tg–s (°C)
71
N.D
79
88
2
69
2+3a
74
2+3c
76
2+3d
78
Tg–s (°C)
N.D: Non detected.
When mixed with 3a, the d-spacing values were 2.17, 1.06, and
0.76 nm (1:1/2:1/3). In contrast, the 1+3a (D-form) system showed
d-spacing values of 3.59, 0.50, and 0.41 nm. When 1 was mixed
with 3a, the resulted gelator system maintains a stronger interdig-
itated bilayer structure in the lipophilic region compared to only 1,
but the broadening in the wide angle region could explain some
weaknesses of the alkyl chain interaction observed in both the
3a–d are all salified and connected to the fibrous network via
amide bonds as in the organogelator.
Differential scanning calorimetry of the gels
1+3a and 1+3a (D-form) systems. Despite our efforts, it was diffi-
The gel-to-sol transition temperatures Tg–s were measured in a
range of temperature between 15 and 90 °C for each toluene gel
sample prepared at 1 wt % of concentration. The values are re-
ported in Table 3.
At this concentration, there is just a slight difference of Tg–s be-
tween 1 and 2. When 1 was mixed with one equivalent of the addi-
tive 3a, 3b, or 3d the Tg–s value increased in the range of 10–20 °C
with the increasing of the alkyl chain length, allowed by the weak-
cult to obtain suitable XRD spectra of the air-dried toluene gel
1+3c, probably due to its low crystallinity. When mixed with 3c
or 3d, in the small angle region, the d-spacing values were 1.98,
1.19, 0.74, and 0.67 nm for 1+3c and 2.68, 1.77, 1.29, and
0.78 nm for 1+3d, which are not in agreement with a simple lamel-
lar structure. Moreover, when mixed with 3c and 3d, the corre-
sponding air-dried xerogels gave intense narrow peaks in the
wide angle region, suggesting that the networks appeared to be
more ordered than that of the 1+3a system.
ened
p–p stacking observed in the two-component systems. Be-
sides, the higher Tg–s value was measured for the 1+3d system.
This result indicates that the Van der Waals interaction of the lipo-
philic fatty tails of 3c or 3d interact modulating the gelation prop-
erties of 1, and finally improve the thermal stabilities of the gel
network. By opposite, with the racemic gelator 2, the moderate in-
crease of the gel-to-sol transition corroborates with the little influ-
ence of the hydrophobic nature of 3a–d reported in the gelation
number graphic (Fig. 4b).
In our theoretical model, it was considered that the self-assem-
bled salt complexes have a bilayer structure with a small region
interdigitated by hydrophobic interactions holding the N-acyl leu-
cines (3a–c) on the periphery. They also have a more complex and
interdigitated stacked bilayer with the salt complex 1+3d.
Rheological studies
In order to determine the influence of the introduction of addi-
tives 3a, 3c, and 3d on the gel elasticity, we examined the flow
behavior and the rigidity of the toluene organogels by measuring
their rheological properties (Fig. 7). In the typical sweep experi-
ment, the variation of storage modulus G0 and loss modulus G00 is
monitored as a function of applied frequency under a constant
Molecular packing and gel network organization
The XRD patterns of the xerogel obtained from toluene gels of 1,
2, and the two-component 1+3a–d systems were measured (Fig. 6).
In the small region, similar d-spacing values of 4.33, 2.21, 1.34, and
Figure 6. XRD patterns of air-dried toluene organogels (a) 1, (b) 1/3a, (c) 1/3c, (d) 1/3d.

F. Delbecq et al. / Tetrahedron Letters 53 (2012) 6588–6593
6593
Figure 7. Frequency dependence of the dynamic storage moduli G0 and the loss moduli G00 of 1 wt % toluene gels of (a) 1; (b) 1+3a; (c) 1+3c; (d) 1+3d.
strain of 0.1%. For materials displaying viscoelastic properties such
as gels, G0 values are greater than G00, characteristic of the elastic
behavior of the system.
Supplementary data
Supplementary data (organic synthesis procedure, 1H NMR data
of gelator 1 and 2, other detailed experimental, FT-IR spectra, rep-
resentative photographs of gels samples, additional gel ability tests
and 1H NMR in the gel state) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.09.107.
According to these results, showing the higher values of G0, the
rigidity of the gel of 1 is more important than we observed in the
presence of 3a, 3c, and 3d. On the other hand, for these two-com-
ponent systems, the storage modulus G0 increases progressively
with the increase of the alkyl chain length of the N-acyl leucines
3a, 3c, and 3d, thus we can affirm the gels are sufficiently robust
in practice. Moreover, at 10 radꢁsꢀ1, the highest measured values
of G0 were respectively 135400, 193500, and 306600 Pa for 1+3a,
1+3c, and 1+3d. These results are consistent with the previous
Tg–s values determined for gel samples of same concentration
and both are only function of hydrophobic interaction improve-
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Conclusion
For concentrations more than 1 wt %, the gelation abilities of the
organogelators 1 and 2 in common organic solvents are efficaciously
modulated by the addition of simple optical N-acyl amino acid, but
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as
L
-alanine or serine derivatives developed in our laboratory.
Based on our results, we intend to develop a new type of DDS by
mixing 1 with a calculated amount of an acidic optically active bio-
active small molecule or peptide such as N-acetyl carnosine. This
kind of system should be used together with the self emulsion drug
delivery system (SEDDS)24,25 and could be efficient at a low pH. The
main limitation of SEDDS or lipid base formulation surfactant dis-
persions is the need for high concentrations of a non-ionic surfac-
tant, generally found between 30–60% in order to form stable
SEDDS formulation containing poorly water soluble compounds.
1 mixed with a lipophilic or hydrophilic chiral compound is ex-
pected to form a robust gel in an oil–water biphasic system or in
alcoholic aqueous solution due to its lack of water solubility. Such
a biocompatible soft material could be readily used in supplemen-
tary experiments such as dialysis in a selected buffer or in vivo lib-
eration of a bioactive molecule.