Stable organogels derived from triazines functionalized with chiral α-amino acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.06.101

Triazines functionalized with three stereogenic α-amino-acidic appendages having at least one amide or hydroxamate function give highly stable organogels in haloalkanes and aromatic solvents, and their gelating ability depends on both structural and stere

Full text of DOI:10.1016/j.tetlet.2008.06.101

Tetrahedron Letters 49 (2008) 5129–5132
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stable organogels derived from triazines functionalized
with chiral
a-amino acid derivatives
*
Raffella Maffezzoni, Matteo Zanda
C.N.R.—I.C.R.M. and Dipartimento C.M.I.C., Politecnico di Milano, Via Mancinelli 7, 20131 Milan, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Triazines functionalized with three stereogenic a-amino-acidic appendages having at least one amide or
Received 28 August 2007
Revised 18 June 2008
Accepted 23 June 2008
Available online 27 June 2008
hydroxamate function give highly stable organogels in haloalkanes and aromatic solvents, and their
gelating ability depends on both structural and stereochemical properties.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Organogel
Triazine
Melamine
a
-Amino acids
Hydroxamic acids
Molecular organogels are one type of soft matter composed of
low-molecular-weight organic molecules (the gelators) forming
three-dimensional networks held together by multiple noncova-
lent interactions, in which organic liquids are immobilized.1 Gela-
tion is a reversible process, and efficient gelators can immobilize
solvent at concentrations less than 1 wt%.
These semisolid materials have generated remarkable interests
both for basic scientific reasons and for technological applications.
Among them, new soft organic materials for special applications,
separations, drug delivery and template synthesis. Although new
gelators are often found more by serendipity rather than by ra-
tional design,2 it is known that derivatives of fatty acids, choles-
tural and stereochemical factors on the formation of the
organogels.8
The triazine-based organogel-forming molecules were prepared
by means of subsequent nucleophilic dechloraminations of the
starting trichlorotriazine by different a-amino acid esters, amides
or hydroxamates as exemplified by the synthesis of 3a (Scheme
1).9
H
Cl
N
Cl
MeO2C
Ph
N
N
Cl
ii
i
N
N
N
N
1
Cl
(78%)
Cl
terol, urea, amino acids and carbohydrates have
a special
proclivity to form organogels.3
H
H
N
H
N
H
N
Triaminotriazines (melamines) have a compact and rigid struc-
ture endowed with high symmetry that can give rise to multiple
non-bonding interactions (Van der Waals interactions and hydro-
gen bonds)4 in well-defined directional preferences.5 We were
therefore surprised to find that no melamine-like gelators are de-
scribed in the literature (except for an example of a binary mela-
mine-barbiturate/cyanurate gelator),6 the only related example
being a family of diaminotriazinecarboxylic acids recently reported
by Wuest and co-workers.7 In this Letter we report the potent
organogel-forming ability of triazines functionalized with three
MeO2C
Ph
N
N
CO2Me
Ph
MeO2C
Ph
N
CO2Me
iii
N
N
N
N
Ph
3f
HN
O
Cl
(96%)
2
(78%)
O
Ph
N
H
H
H
N
MeO2C
Ph
N
N
CO2Me
Ph
N
N
iv
HN
O
(70%)
a-amino acid substituents, and a study on the influence of struc-
OH
N
H
3a
Scheme 1. Synthesis of the organogel-forming triazines. Reagents and conditions:
(i) -Phe-OMe (1 equiv), NaHCO3, acetone/H2O, 0 °C, 1 h; (ii) -Phe-OMe (1 equiv),
L
L
* Corresponding author. Tel.: +39 0223993084; fax: +39 0223993080.
E-mail address: matteo.zanda@polimi.it (M. Zanda).
NaHCO3, acetone/H2O, rt, overnight; (iii) Gly-NHOBn (1 equiv), DMSO, DIPEA,
120 °C, 2 h; (iv) H2/Pd, MeOH, rt, 2 h.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.101

5130
R. Maffezzoni, M. Zanda / Tetrahedron Letters 49 (2008) 5129–5132
A number of solvents were screened in order to investigate the
gelating properties of triazines 3–8 (Scheme 2). None of them was
found to be able to gelate alcohols (methanol, ethanol and isopro-
panol gave always solutions), ethers (diethyl ether and diisopropyl
ether were poorly solubilizing, whereas THF and dioxane gave
solutions), alkanes (these triazines are poorly soluble in hexane
and cyclohexane), acetone and acetonitrile (they mostly gave solu-
tions), triethylamine and water (very poor solubility).
Formation of organogel was observed in ethyl acetate for the
compounds 3b,c at a rather high concentration of 3% w/w. Forma-
tion of stable gels was observed with haloalkanes and aromatic sol-
vents, in particular toluene, for most triazines 3–8 (Table 1).10 As it
can be seen in Figure 1, the gel formed by 3a in CHCl3 is very clear
at a concentration of 1 wt%, and becomes progressively more tur-
bid at higher concentrations.
Figure 1. Gels formed by 3a in CHCl3 at different concentrations at rt. From left:
CHCl3 only, 1.0, 1.5, 2.0, 2.5 and 3.0 wt%.
Table 1 shows that most triazines having an amide or hydroxa-
mate function form gels in toluene, with the exception of the tert-
butyl ester derivative 3d and the bis-glycine derivative 5, which
are substantially unable to gelate. Compounds missing the amide
or the hydroxamate function, such as the triester derivatives 7
and 8, are also unable to gelate. Interestingly, also the chlorotria-
zine 6 can form gels in CH2Cl2 and toluene at a concentration of
2 wt%, but the gel is rather unstable and the compound tends to
form a precipitate. Chiral bis-phenylalanine triazines methyl or
ethyl esters, which bear a glycine functionalized as hydroxamate
(3a) or amide (3b,c), have the strongest capacity to give gels in
chloroalkanes, in aromatic solvents and even in ethyl acetate. In
contrast, the corresponding achiral meso-structures 4a,b have low-
er gelating capacity in chloroalkanes, but they give very strong gels
in toluene.
The stability and gel–sol transition temperatures of the organo-
gels formed by chiral 3a,b and meso 4b in different solvents were
studied in detail by means of the ‘falling-ball’ method,11 namely by
positioning a steel sphere having 2 mm of diameter and 130 mg of
weight on the surface of the organogel, and by monitoring its pen-
etration until the bottom of the gel sample upon increasing the
temperature. It is worth noting that the meso-compound 4b in tol-
uene gives organogels having high thermal resistance with mp
above 100 °C. The trends for the gel–sol transitions of 3b and 4b
in toluene at different temperatures are reported in Figure 2.
To evaluate the influence of the stereochemical purity on the
gel-forming capacity of these triazines, we checked the behaviour
of racemic compounds 3a and 3b in toluene, which showed sur-
prising differences with respect to the enantiomerically pure com-
pounds. Racemic 3a in toluene at 2 wt% concentration formed a
more transparent gel having lower gel–sol transition temperature
with respect to enantiopure 3a, namely 52 2 °C versus 57 2 °C
(see Table 2). In contrast, racemic 3b under the same conditions
formed a more turbid gel having higher gel–sol transition temper-
ature with respect to enantiopure 3b, namely 84 1 °C versus
77 1 °C (see Table 2).12 Clearly, the strikingly different behaviour
of these molecules depends on the presence of either the hydroxa-
H
N
H
N
H
N
H
N
R2O2C
N
CO2R2
MeO2C
N
CO2Me
R
N
N
R
Bn
N
N
Bn
R1
HN
HN
R1
O
N
H
O
N
H
R = Bn, R1 = OH, R2 = Me
4a R1 = OH
3a
3b R = Bn, R1 = H, R2 = Me
3c R = Bn, R1 = H, R2 = Et
3d
= tert-Bu
4b
R
1 = H
R = Bn, R1 = OH, R2
R = iso-Bu, R1 = H, R2 = Me
3e
H
N
H
N
H
N
MeO2C
Ph
N
Cl
EtO2C
N
CO2Et
N
N
N
N
Ph
HN
O
HN
O
OH
OH
N
H
N
H
6
5
H
H
N
H
H
MeO2C
N
N
CO2Me
MeO2C
N
N
N
CO2Me
Bn
N
N
Bn
Bn
N
N
Bn
HN
Bn
HN
CO2Me
CO2Me
7
8
Scheme 2. Set of triazine-based structures investigated for their organogel-forming
ability.
Table 1
120
100
80
Gel forming capacity of triazines 3–8 in different solvents at 3 wt % and rt
Triazine
CH2Cl2
CHCl3
(ClCH2)2
Toluene
EtOAc
3a
3b
3c
3d
3e
4a
4b
5
Gel
Gel
Gel
Sol
Sol
Sol
Sol
Sol
Gela
Sol
Sol
Gel
Sol
Gel
Sol
Sol
Sol
Sol
Sol
Prec
Sol
Sol
Gel
Gel
Gel
Sol
Sol
Sol
Sol
Sol
Prec
Sol
Sol
Gel
Gel
Gel
Sol
Gel
Gel
Gel
Wgel
Gela
Sol
Sol
Gel
Gel
Sol
Sol
Sol
Sol
Sol
Prec
Sol
Sol
60
3b
40
4b
6
7
8
20
0
2
4
6
Sol
conc %(w/w)
a
Key: g = gel; sol = solution; wgel = weak gel that is unable to sustain the steel
ball on the surface. A precipitate tends to form at a concentration of 2 wt%.
Figure 2. Gel–sol transitions of 3b and 4b in toluene at variable temperatures.

R. Maffezzoni, M. Zanda / Tetrahedron Letters 49 (2008) 5129–5132
5131
Table 2
10000.00
Gel–sol transition temperatures (°C) of gels formed from some triazines in different
solvents
Triazine (wt%)
CH2Cl2
CHCl3
(ClCH2)2
Toluene
EtOAc
1000.00
100.00
10.00
3a
2.0
3.0
5.0
0.05
0.2
0.5
1.0
2.0
3.0
5.0
0.2
0.5
1.0
2.0
3.0
41
43
44
1
1
1
30
33
35
1
1
1
35
36
38
1
1
1
57
58
61
2
1
1
Sol
Sol
Sol
Sol
Sol
Sol
Sol
Sol
Wgel
3b
Sol
Sol
Sol
Sol
Wgel
Wgel
Sol
Sol
Sol
Sol
Sol
Sol
Wgel
Sol
Sol
Sol
Sol
Sol
Sol
Sol
Wgel
Wgel
Sol
Sol
Sol
Sol
Sol
Wgel
51
64
70
77
1
1
1
1
1
2
78
81
G'
35
2
41
2
4b
Sol
Sol
Sol
Sol
Sol
Wgel
72
86
96
103
Sol
Sol
Sol
Sol
Sol
G"
2
2
1
2
1.00
Sol
Sol
Sol
1.00
10.00
100.00
1000.00
stress (Pa)
Key: sol = solution; wgel = weak gel that is unable to sustain the steel ball on the
surface.
Figure 4. Viscoelastic behaviour of the organogel formed from compound 3b in
toluene (1 wt%) at 20 °C.
To measure the organogel rigidity and its response to stress, a
rheological analysis of the gel formed from compound 3b in tolu-
ene (1 wt%) at 20 °C was conducted using a rotational stress-con-
trolled rheometer (constant oscillation frequence = 1 Hz).14 As
shown in Figure 4, the storage (elastic) modulus (G0) is greater than
the loss (viscous) modulus (G00) showing that this is a well-struc-
tured system, having the dominant elastic behaviour typical of a
gel. The G0 and G00 values remain constant in a wide range of strain
below the critical value of 560 Pa. The equilibrium value for
mic acid or the amide function of 3a and 3b, respectively, which
probably give rise to different supramolecular structures of these
triazines, depending on their enantiomeric purities.
Since triesters 7 and 8 are unable to gelate, it clearly appears
that the amide and hydroxamic acid functions of 3–6 are essential
for the supramolecular assembly of the triazine molecules, proba-
bly contributing to a network of intermolecular hydrogen-bonds.13
The C2-symmetry of the organogel-forming triazines 3 might be
another important factor, as shown by the fact that low-symmetry
molecules like 5 and 6 have lower organogelating power, as well as
G0eq ¼ ca. 104 Pa is one order of magnitude greater than that for
00
G
¼ ca.1100 Pa.
eq
Cs-symmetrical meso-structures 4a, b.
p-Stacking interactions
In summary, we have identified the first family of melamine-
involving the phenyl groups might be as well important, since
Leu-derived 3e has lower organogelating properties. Finally, the
steric bulk of the ester function seems to hinder the organogel for-
mation, as shown by the fact that tert-Bu ester 3d is unable to
gelate.
SEM morphologic analysis of the xerogel obtained from 4b
(0.5 wt% in toluene) showed a dense network of fibres having a
diameter of about 100 nM (Fig. 3), which is clearly responsible
for the encapsulation of the molecules of solvent, and therefore
for the formation of the organogel.
based chiral molecules having very good organogelating proper-
ties. The modular structure and smooth synthesis of these triazines
substituted by three amino-acidic appendages make these organo-
gelators a promising class of biomimetic, peptide-like compounds
having potential applications in biomedicinal field.
Acknowledgements
We acknowledge financial support from the National Research
Council and Politecnico di Milano. We thank Professor Pio Forzatti
and his group for support with the rheological analyses.
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Figure 3. SEM image of the xerogel obtained from 4b (0.5% w/w in toluene).

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