A family of strong low-molecular-weight organogelators based on aminoacid derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.10.139

A new family of potent aminoacid-type organogelators obtained via an easy and unexpensive way is described. We demonstrated that structural variations onto the side chains of the aminoacid derivatives allowed modulations of the gelation properties. The or

Full text of DOI:10.1016/j.tetlet.2004.10.139

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9521–9524
A family of strong low-molecular-weight organogelators based on
aminoacid derivatives
b
a
Nicolas Brosse,a, Danielle Barth and Brigitte Jamart-Gregoire
*
´
a
´
Laboratoire de Chimie Physique Macromoleculaire, UMR 7568, ENSIC-INPL, BP 451, 54001 Nancy, France
b
´
Laboratoire de Thermodynamique des Milieux Polyphases, ENSIC-INPL, BP 451, 54001 Nancy, France
Received 1 October 2004;revised 21 October 2004;accepted 26 October 2004
Available online 11 November 2004
Abstract—A new family of potent aminoacid-type organogelators obtained via an easy and unexpensive way is described. We dem-
onstrated that structural variations onto the side chains of the aminoacid derivatives allowed modulations of the gelation properties.
The organogelators bearing a benzyl or an isopropyl group (compounds 1e, 2a, and 2c) are able to provide gelation of apolar sol-
vents at very low concentration (60.2wt%) and to form thermostable gels.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ative (1a, R = CH2Ph, P = Z) exhibited the property to
gelate at low concentration the solvent used for its prep-
aration (1% weight in toluene). Several examples of ami-
noacid-type organogelators have been reported in the
literature such as small peptides or pseudopeptides,1e–i
cyclopeptides,1j and bis-urea.1k,l Taking into account
data concerning these compounds and the chemical
structure of 1a, network of intermolecular hydrogen
bonds as well as p–p stacking and hydrophobic interac-
tions could be important contributors to the aggregation
process.
The organogelation phenomenon exhibited by low-
molecular-weight molecules is the subject of increasing
attention.1 Thermoreversible physical gels are generally
formed by a self-aggregation leading to the formation
of fibrous network imprisoning the solvent, noncovalent
cross-links among the nanofibers creating the three-
dimensional network. The supramolecular nature of this
phenomenon has been demonstrated: gelator molecules
are assembled through noncovalent interactions (hydro-
gen bonding, van der WaalÕs, p-stacking. . .).1,2 How-
ever, the relationship between the chemical structure of
an organogelator and its gelation properties in a given
solvent is not clearly established;discovery of new gela-
tors remains mainly fortuitous and the design of a define
gelator is not yet feasible. Furthermore, gels have
numerous industrial applications in areas such as cos-
metic, lubrification, paper, and health care.1a For these
applications, the development of unexpensive but effi-
cient organogelators is of great interest.
2. Results and discussion
To help understand the organogelation phenomenon
and to define a new group of structurally related
gelators, a series of aminoacid derivatives 1 and 2
(Scheme 1) was prepared in order to try to establish a
During investigations dealing with the synthesis of new
families of pseudopeptides, we have demonstrated that
N-protected phthaloylhydrazide aminoacids 1 can be
used as acidic partners in the Mitsunobu protocol.3
Unexpectedly, we observed that the phenylalanine deriv-
O
O
N
R
H
R
H
H
N
H
b
N
N
a
PHN
PHN
O
1
O
O
O
2
P=PhCH2OCO- (Z) or CH2=CH-CH2OCO (Alloc)
R = CH2Ph, Ph or CH2CH(CH3)2
(see table)
Keywords: Organogel;Organogelator;Electronic microscopy.
*
Corresponding author. Tel.: +33 3 83 17 53 28;fax: +33 3 83 37 99
77;e-mail: nicolas.brosse@ensic.inpl-nancy.fr
Scheme 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.139

9522
N. Brosse et al. / Tetrahedron Letters 45 (2004) 9521–9524
• the sol–gel phase transfer temperature (Tm in ꢁC)
R
H
a, b
c
R
H
1 or 2
where the gel (at a concentration of 0.5wt%) melts
into solution. These data were established by rheol-
ogy, which is described as the more accurate and con-
venient method.4
H2N
COOCH3
PHN
CONHNH2
Scheme 2. Reagents and conditions: (a) ZCl or AllocOSu, 1equiv;(b)
NH2NH2, 3equiv, MeOH, rt, 18h;(c) phthalic or naphthalic anhy-
dride, 1equiv, toluene, reflux.
It appears from this study that modifications of the
hydrophobic parts of the compounds do not affect their
organogelation ability, which seems to be mainly gov-
erned by the polar part of the amphiphilic molecules.
structure–physical properties relationship. This new
kind of gelling agents possesses the advantage to be very
easy to prepare starting from unexpensive starting mate-
rials and that many structural variations can be intro-
duced as P and R.
1
We performed some H NMR studies on 1d in CCl4/
C6D6 (4/1) at different temperatures between 25ꢁC
(gel) and 70ꢁC (solution) (see Electronic Supplementary
Information) in order to follow the temperature-depend-
ent chemical shifts of the two NH protons (Ha and Hb,
see Scheme 1). Very interestingly, we observed (see Fig.
1) that the chemical shift of Ha is quite invariant up to
the sol-to-gel transfer temperature (50ꢁC) suggesting
its implication in a strong hydrogen bond and is shifted
upfield at higher temperature. On the contrary, a down-
field shift in 25–50ꢁC range and upfield shift at higher
temperature was observed for Hb. As previously re-
ported,5 these latter chemical shift trends could corre-
Compounds 1 and 2 were prepared in three steps from
(S)-aminoacid methyl esters according to the general
procedure described in the Scheme 2.3a The gels were
obtained by heating together the solvent and the organ-
ogelator (0.18–2.5wt%) in a flask fitted with a reflux
condenser until the dissolution of the solid was com-
plete. The solution was transferred into a closed vial
and cooled to 0ꢁC. Mainly, the formation of the gel oc-
curred within several minutes, if any.
spond to
a
weaker hydrogen bond network.
Considering these results, it is possible to postulate that
the formation of the aggregates probably occurs
through the build up of a strong hydrogen bonds net-
work (involving the more acidic NHa proton3a) but also
of weaker hydrogen bonds one involving the NHb
proton.
The organogelation ability of compounds 1 and 2 in
apolar solvents is described in the Table 1. The thermo-
stability of the gels has been evaluated considering two
factors:
• the critical gelation concentration (CGC in wt%)
where the sol-phase changes into gel-phase (stable
at room temperature),
Compounds 1 or 2 bearing aromatic or aliphatic
hydrophobic side chain R can equally cause gelation
Table 1. Organogelation ability of compounds 1 and 2
Compound
R
P
Toluene
CGCb
Toluene/cyclohexane 1/1
CCl4
Statea
Tm (ꢁC)c
Phasea
CGCb
Tm (ꢁC)c
Statea
CGCb
Tm (ꢁC)c
1a
1b
1c
1d
1e
2a
2b
2c
2d
CH2Ph
Ph
Z
CG
WG
CG
WG
P
1
NVd
80
I
I
Z
0.5
2.5
0.5
I
I
CH2CH(CH3)2
CH2Ph
Z
NV
54
CG
CG
I
0.5
0.35
55
68
I
CG
Alloc
Z
0.25
0.2
57
78
CH(CH3)2
CH2Ph
Ph
I
Z
CG
P
0.18
80
I
I
Z
I
I
CH2CH(CH3)2
CH2Ph
Z
Alloc
CG
CG
0.5
0.35
45
66
CG
I
0.2
92
WG
I
a CG = clear gel, WG = white gel, P = solution upon heating, precipitate at room temperature;I = insoluble.
b Critical gelation concentration in wt%.
c Determined by rheology4 for a concentration of 0.5wt%.
d No value (CGC > 0.5%).
Nb
Na
5.4
5.35
5.3
8.7
8.6
8.5
8.4
8.3
5.25
0
50
temperature (°C)
100
0
50
temperature (°C)
100
Figure 1. Variation of the chemical shift of NHa and NHb protons of 1d in CCl4/C6H6 recorded between 25ꢁC (gel) and 70ꢁC (solution).

N. Brosse et al. / Tetrahedron Letters 45 (2004) 9521–9524
9523
Figure 2. SEM pictures of the dried toluene–gels: · 20,000 (a) 2a, (b) 1b (scale bar is 2lm); · 40,000, (c) 2a, (d) 1b (scale bar is 1lm).
of toluene. On the contrary, a relative small constitu-
tional change occurred onto the lateral chains resulted
in a dramatic change of the gelation properties: com-
pounds 1e and 2b lacked any gelation abilities because
of a tendency to crystallize whereas homologous com-
pounds 1c and 2a were able to gelify efficiently the
toluene.
ature (Tm) of the corresponding gels are high: impres-
sively, for a concentration of only 0.2wt%, gel from 2c
in CCl4 can be heated to the boiling point of the solvent
without sol-to-gel transition;in the same way, at a con-
centration of 2wt%, the compound 2a forms a gel in tol-
uene which can be heated up to 116ꢁC (bp of the
solvent).
The area of the conjugated systems at the C- and N-ter-
minal parts of the compounds was analyzed in term of
gelation ability (CGC and Tm): compound 2a bearing
a benzyl group at the N-terminal part has better gelation
ability than 2d bearing an allyl group (Z ! Alloc). In
the same way, the organogelation behavior of com-
pounds 2 possessing a naphthalimide group in the C-ter-
minal part was higher than those of the phthalimide
derivatives 1. This observation could underline the
importance of the p stacking in the gelation process of
compounds 1 and 2.
In the table is reported a visual examination of the gels:
clear gels (which were mainly transparent) and white
gels (for which a white opacity was observed) were dis-
tinguished. It appears that both the structure of the
organogelator and the nature of the solvent can affect
the turbidity of the gel. According to previous works,6
it is assumed that the optical aspect is related to the crys-
tallinity of the gels. Thus, the electron micrographs re-
veal a great difference between a clear gel (from
compound 2a in toluene) and a white gel (from com-
pound 1b in toluene) in the fiber dimensions and in
the network structure. Figure 2 displays pictures of
aerogels obtained from toluene gels (c = 0.5wt%) dried
under supercritical conditions: 2a exhibits a fibrous
aggregated morphology (with fibers length of several
lm, pictures a and c) whereas 1b exhibits a lamellar
aggregation mode for which the fibers length are signif-
icantly shorter and the fibers tend to be more aggregated
(pictures b and d).
Interestingly, properties of the gels can be altered by a
small change of the solvent composition and polarity:
for compounds 1c,d, and 2c possessing only two aro-
matic moieties, the best gelling ability was observed in
a mixture cyclohexane/toluene (1/1) or in CCl4 whereas
the other compounds (bearing three aromatic groups)
were not soluble in these solvents. This observation
shows that the presence of the aliphatic moiety seems
to enhance the gelation of aliphatic solvent, the sol-
vent–gelator affinity affecting the solubility and the mor-
phology of the fibers. Thus, it appears that the CGC for
2a in toluene and for 2c in a mixture cyclohexane/tolu-
ene or in CCl4 are very low (respectively, 0.18 and
0.20wt%);moreover, the sol–gel phase transfer temper-
3. Conclusion
To conclude we have defined a new family of potent
aminoacid-type organogelators of apolar solvents. We
have shown that the polar part of the molecules seems

9524
N. Brosse et al. / Tetrahedron Letters 45 (2004) 9521–9524
to govern the aggregation of individual compounds via a
hydrogen bonds network while the hydrophobic parts
could affect the intrinsic flexibility and the fiber–fiber
interactions. In accordance with previous works,7 struc-
tural variations of the side chain of the aminoacid affect
the solubility and the efficiency of the intermolecular
overlap of the aggregation process and so allowed mod-
ulations of the gelation properties. Thus, in an aromatic
solvent, the p-stacking appears to be an important
contributor to the gelation phenomenon whereas the
presence of aliphatic moiety seems to enhance the
gelation of aliphatic solvent. Depending on the nature
of the gelator used, the structure of the aggregates
ranges from a fibrous to a lamellar morphology. Some
of the organogelators described in this paper are able
to form, even at low concentration, gels with good
thermal stabilities.
Acknowledgements
The authors wish to thank EEIGM (Ecole Europeenne
´
´
´
´
dÕIngenieurs en Genie des Materiaux) and Pierre Bec-
king for his assistance with microscopy experiments.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.10.139. NMR data and experimental procedure
for the supercritical drying of the organogels are availa-
ble in Supporting informations.
References and notes
1. Review: (a) Terech, P.;Weiss, R. G. Chem. Rev. 1997, 97,
3133–3159;(b) Estroff, L. A.;Hamilton, A. D. Chem. Rev.
2004, 104, 1201–1217;(c) Selection of recent papers:
Schmidt, R.;Adam, F. B.;Michel, M.;Schmutz, M.;
4. Experimental
´
Decher, G.;Me sini, P. J. Tetrahedron Lett. 2003, 44, 3171–
4.1. Procedure for the preparation of 2a
3174;(d) Suzuki, M.;Nigawara, T.;Yumoto, M.;Kimura,
M.;Shirai, H.;Hanabusa, K. Tetrahedron Lett. 2003, 44,
6841–6843;(e) Becerril, J.;Hanabusa, K.;Okui, K.;
Karaki, K.;Koyama, T.;Shirai, H. J. Chem. Soc., Chem.
Step (a): L-Phenylalanine methylester hydrochloride
(10.75g, 50mmol.) was dissolved in aqueous saturated
NaHCO3 solution (200mL) and benzylchlorocarbonate
(8.5g, 50mmol) was added under vigorous stirring. Stir-
ring was continued overnight. The solution was ex-
tracted with ether (three times). The combined organic
layers were washed with HCl 1N, dried under MgSO4,
and concentrated at reduce pressure. The excess of benz-
ylchlorocarbonate was removed using a short column
chromatography (eluent: petroleum ether;the product
was chromatographed with 40% EtOAc/petroleum
ether) to give 14g (90%) of pure product. Step (b):
Hydrazine hydrate (5g, 100mmol) was added to a solu-
tion of N-benzyloxycarbonyl-L-phenylalanine methyl
ester (10g, 32mmol) in methanol (100mL). The mixture
was stirred overnight at room temperature and the
hydrazide was collected by filtration, washed with meth-
anol, and dried (7.8g, 78%). Step (c): The hydrazide
derivative (2g, 6.3mmol) was added to a suspension of
naphthalic anhydride (1.26g, 6.3mmol) in toluene
(200mL) and the resulting mixture was refluxed, the
water formed during the reaction was trapped in a
Dean–Stark receiver. After 6h, the solution was cooled
and quickly transformed into a gelatinous mass, which
was evaporated in vacuo to dryness. The solid residue
was recrystallized in CHCl3. 1H NMR (300MHz,
CDCl3) of 2a: d 8.85 (s, 1H), 8.65–8.45 (m, 2H), 8.20
(d, 2H), 7.80–7.60 (m, 2H), 7.45–7.10 (m, 10H), 5.63
(m, 1H), 5.15–5.00 (m, 2H), 5.00–4.75 (m, 1H), 3.38
(dd, 1H), 3.18 (dd, 1H).
´
Commun. 1992, 1371–1372;(f) Carre , A.;Le Grel, P.;
Baudy-FlocÕh, M. Tetrahedron Lett. 2001, 42, 1887–1889;
(g) Makarevic, J.;Jokic, M.;Frkanec, L.;Katalenic, D.;
Zinic, M. J. Chem. Soc., Chem. Commun. 2002, 2238–2239;
(h) Okabe, S.;Ando, K.;Ihara, H.;Sakurai, T.;Yamada,
T.;Hashimoto, T.;Takafuji, M.;Sagawa, T.;Hachisako,
H. Langmuir 2002, 18, 7120–7123;(i) Hanabusa, K.;
Shibayama, M. J. Polym. Sci. B 2004, 42, 1841–1848;(j)
Escuder, B.;Luis, S. V.;Miravet, J. F.;Querol, M. J. Chem.
Soc., Chem. Commun. 2002, 738–739;(k) Brinksma, J.;
Feringa, B. L.;Kellogg, R. M.;Vreekler, R.;van Esch, J.
Langmuir 2000, 16, 9249–9255;(l) Hamilton, A. D.;Wang,
G. Chem. Eur. J. 2002, 8, 1954–1961.
2. Koumoto, K.;Yamashita, T.;Kimura, T.;Luboradzki, R.;
Shinkai, S. Nanotechnology 2001, 12, 25–31;Hamada, D.;
Yanagihara, I.;Tsumoto, K. Trends in Biotechnol. 2004, 22,
93–97;de Loos, M.;van Esch, J.;Kellog, R. M.;Feringa,
B. L. Angew. Chem., Int. Ed. 2001, 40, 613–616.
´
3. (a) Brosse, N.;Pinto, M.-F.;Jamart-Gre goire, B. J. Org.
Chem. 2000, 65, 4370–4374;(b) Brosse, N.;Pinto, M.-F.;
´
Bodiguel, J.;Jamart-Gre goire, B. J. Org. Chem. 2001, 66,
2869–2873;(c) Brosse, N.;Pinto, M.-F.;Jamart-Gre goire,
´
B. Eur. J. Org. Chem. 2003, 23(24), 4757–4764.
4. Terech, P.;Rossat, C.;Volino, F. J. Colloid Interface Sci.
2000, 227, 363–370.
5. Makarevic, J.;Jokic, M.;Raza, Z.;Stephanic, Z.;Kojic-
Prodic, B.;Zinic, M. Chem. Eur. J. 2003, 9, 5567–5580.
6. Terech, P.;Pasquier, D.;Bordas, V.;Rossat, C. Langmuir
2000, 16, 4485–4494.
7. Terech, P.;Bouas-Laurent, H.;Desvergne, J.-P. J. Colloid.
Sci. 1995, 174, 258–263.