The triazine ring as a scaffold for the synthesis of new organogelators

Article abstract of DOI:10.1016/j.tetlet.2007.12.124

The synthesis of new organogelators based on a triazine nucleus is described together with the analysis of the properties of the main compound 15. This compound revealed an efficient organogelator in both polar and apolar solvents and represents a promisi

Full text of DOI:10.1016/j.tetlet.2007.12.124

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1701–1705
The triazine ring as a scaffold for the synthesis of new organogelators
a,
a
a
a
b,
*
*
Stefano Cicchi , Giacomo Ghini , Sara Fallani , Alberto Brandi , Debora Berti
,
Francesca Betti b, Piero Baglioni b
a
`
Dipartimento di Chimica Organica ‘Ugo Schiff’, Universita di Firenze and INSTM, Via Della Lastruccia 13, Italy
`
Dipartimento di Chimica, Universita di Firenze and CSGI, Via Della Lastruccia 3, 50019 Sesto Fiorentino, Italy
b
Received 28 September 2007; revised 20 December 2007; accepted 21 December 2007
Available online 8 January 2008
Abstract
The synthesis of new organogelators based on a triazine nucleus is described together with the analysis of the properties of the main
compound 15. This compound revealed an efficient organogelator in both polar and apolar solvents and represents a promising precursor
of other functionalized organogelators.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Organogel; Triazine; Pyrrolidine; Self-assembly
Organogels, gels formed by low molecular weight
organic molecules, are attracting interest due to their pecu-
liar behavior as supramolecular systems1 and for the appli-
cations that they promise.2 Their properties and the
mechanisms, which are responsible for their formation,
have been long studied although far from being fully
described.3 Particular attention is now posed on the appli-
cation of these materials. The main goal is the development
of gels, which are responsive to external stimuli such as
light, temperature, pH variations, or the presence of pollu-
tants. To exploit the potential applications it is necessary to
produce organogelators, which are able to form stable gels
in several different conditions and which can be appended
with large molecular fragments maintaining the gelation
ability. This approach will allow the obtainment of many
different gels starting from the same organogelator, each
of them showing peculiar properties. Examples of gelators
are known and the synthetic effort is directed toward their
modification introducing reacting centers at the periphery4
or at the core.5,2a–d In this work, we describe our recent
efforts toward the synthesis of an efficient gelating scaffold,
able to form stable gels supporting a variety of molecular
fragments. We have recently introduced a new organogel-
ator, compound 2,6 based on a pyrrolidine nucleus substi-
tuted with two carbamate groups bearing C12 chains
(Fig. 1). Some preliminary studies showed that the inter-
twining fibers forming the gels, obtained with 2 in cyclo-
hexane, are based on the formation of hydrogen bond
chains between the carbamate groups.6a This was suggested
by a temperature dependent FT-IR study as well as by an
X-ray analysis.6b The length of the aliphatic chains is an
important parameter, since compound 1 (n = 7) does not
show any gelating ability.
NH
HN
O
n
n
O
O
O
N
R
1 R = Bn, n = 7
2 R = Bn, n = 11
3 R = H, n = 7
4 R = H, n = 11
*
Corresponding authors. Tel.: +39 0554574496; fax: +39 0554573531
(S.C.); tel.: +39 0554573038 (D.B.).
E-mail addresses: stefano.cicchi@unifi.it (S. Cicchi), debora.berti@
unifi.it (D. Berti).
Fig. 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.124

1702
S. Cicchi et al. / Tetrahedron Letters 49 (2008) 1701–1705
The main feature of compound 2 is represented by the
substituent is not a guarantee for the gelation ability as
demonstrated by compounds 7 and 9.
chance to remove, by catalyzed hydrogenation, the benzyl
group affording the secondary amine 4, a useful functional-
ity for grafting molecular fragments (Fig. 1). The insertion
of a variety of substituents onto the nitrogen atom repre-
sented, beside the possible application, a good test for the
efficiency of the organogelator and we started the synthesis
of a series of derivatives whose structure is reported in
Figure 2. As can be seen from Table 1, the substitution
of the benzyl moiety with other groups not always pre-
served the ability to form organogels. The simple substitu-
tion of the benzyl group with an allyl moiety, like in
compound 5, removes the gelation ability suggesting the
role of the p-stacking interactions in the columnar disposi-
tion of 2. Nevertheless, the simple presence of an aromatic
Among the five derivatives listed in Figure 2, only com-
pound 6 revealed a good gelator even better than com-
pound 2 itself. As shown in Figure 3, the differential
scanning calorimetry (DSC) measurements showed an high
gel–sol transition temperature (61.5 °C for 6 vs 36 °C for
2); this transition is first-order, characterized by a finite
DH (DH = 1.17 Kcal/mol).
The simple gelator 2 revealed to be extremely sensitive to
the nature of the molecular fragments grafted onto the
nitrogen atom. We reasoned that assembling more than
one gelating unit around a central scaffold could afford
more efficient and versatile organogelators. The scaffold
should also carry a suitable side arm for easily grafting
other different molecular fragments. A suitable candidate
was identified in cyanuric chloride since its well-known
reactivity allows the insertion of up to three different sub-
stituents on the heteroaromatic ring.7 This approach might,
in principle, afford a large variety of different gelators vary-
ing the nature and number of gelating units and the nature
and length of side arms as long as they possess a nucleo-
philic center to react with the triazine ring.
To start this study, we chose to assemble two units of
pyrrolidine 3 around the triazine ring and used the third
reacting center of the heteroaromatic ring for the insertion
of an ethylene glycol unit as a side arm. The synthesis of
the new triazine derivatives 14 and 15 is described in
Scheme 1. Practically, it resulted more conveniently to
insert the oxygenated moiety initially. The ethylenglycol
monobenzyl ether (12), obtained through the reaction of
benzylchloride with ethyleneglycol catalyzed by Cu(A-
cAc)2,8 was reacted with cyanuric chloride (10) to afford
derivative 13 (Scheme 1). Finally 13 was reacted with
pyrrolidine 3 to afford in a moderate yield gelator 14.
Table 1
Gelating ability
Comp.
Gel formationa
1
2
—
Acetonitrile (0.3)
Cyclohexane (0.2)
—
Acetonitrile (0.3)
Cyclohexane (0.2)
—
Cyclohexane (1.0)
—
Acetonitrile (1.0)
Cyclohexane (0.1)
Xylene (0.2)
Diisopropylether (0.4)
Acetonitrile (0.3)
Cyclohexane (0.1)
Xylene (0.3)
Diisopropylether (0.4)
Hexane (0.4)
5
6
7
8
9
14
15
16
17
Cyclohexane (0.1)
Xylene (0.3)
Acetonitrile (0.4)
Cyclohexane (0.1)
Toluene (1.0)
Isopropanol (0.4)
6 1st cycle heating
15 1st cycle heating
15 2nd cycle heating
a
Solvent (critical concentration w/v %).
-0.70
-0.75
-0.80
R
O
R
R
O2S
R
N
O
N
6
5
7
8
NO2
R
N
O
R
NH
11
HN
11
O
O
60
70
80
90
100
O
O
T [°C]
R =
9
N
O
Fig. 3. DSC thermograms of compounds 6 and 15. The baseline DSC
trace corresponding to 6 has been offset for graphical purpose.
Fig. 2.

S. Cicchi et al. / Tetrahedron Letters 49 (2008) 1701–1705
1703
Cl
Cl
N
N
10
N
N
Cl
N
Cl
BnCl
O
THF, DIPEA
Cu(AcAc)2
HO
Cl
N
O
HO
O
12
OH
0 °C, 60 h
49%
ref. 8
11
13
n
n
HN
O
NH
O
O
O
3 or 4
O
O
N
N
O
N
MW, Toluene
DIPEA
HN
n
NH
n
O
N
N
O
O
14 n = 7 30%
15 n = 11 34%
Scheme 1.
The use of microwaves for this step (100 W, Toluene, 15 m)
revealed more efficient respect to conventional heating
(refluxing toluene, 5 h, 10% yield). The gelating properties
of 14 were studied in several solvents. As can be seen from
Table 1, compound 14 can gel different solvents and in the
case of cyclohexane, the critical concentration is very low.
Gels obtained in cyclohexane and xylene are very stable
and transparent.
transition.11 However, the calorimetric peak becomes more
symmetric and narrow upon annealing (cooling and sub-
sequent heating at 1 °C/min) of the sample (Fig. 3, dotted
line), while the maximum of the endothermic transition is
practically unaffected, ruling out the evaporation of the
solvent during the measurement or sample damage. We
have attributed the irregular shape observed during the first
scan, to the possible presence of inhomogeneities, probably
due to the transfer of the highly viscous gel into the
measurement pan. The steeper shape of the endothermic
peak has been interpreted as a first-order transition.12
To fulfill the original aim, to produce a gelating scaffold
that can be substituted with different molecular fragments,
the benzyl protecting group had to be removed. A simple
Pd(OH)2/C catalyzed hydrogenolysis of 15 afforded alco-
hol 16 in good yield (Scheme 2). Alcohol 16 maintained
From a comparison between the gelating ability of com-
pounds 1 and 2, it was obvious that the length of the alkyl
chains plays a role in the formation and stability of the gel.
For this reason compound 13 was reacted with pyrrolidine
4 to afford compound 15.9 Compound 15 revealed an excel-
lent gelator in several solvents although the difference with
14 is not dramatic. The most important improvement was
the new value for the critical concentration in acetonitrile
(1% for 14 vs 0.33% for 15) and the ability to form gel also
in hexane. The critical concentration of 15 in the tested sol-
vents ranged from 0.78 to 3.12 mM, values that indicate
compound 15 as a ‘supergelator’.10 Compound 15 was
chosen as the lead compound and some of its properties
were analyzed. As already observed for compound 2,6a also
the FT-IR spectra of 15 showed significant variations
changing from CH2Cl2 solution to the cyclohexane gel.
The main differences involve the N–H stretching [3447
(CH2Cl2) vs 3330 cmꢀ1 (cyclohexane gel)] and the C@O
stretching of the carbamate groups [1727 (CH2Cl2) vs
1697 cmꢀ1 (cyclohexane gel)]. The DSC measurements
were performed in sealed aluminum pans. The high gel–
sol transition temperature (Tgel–sol = 82.2 °C, slightly
above the boiling point of cyclohexane), corresponding to
the maximum of the endothermic peak (Fig. 3, solid line),
indicates a remarkable strength of the gel structure, while
the irregular, broad and multicomponent profile of the
peak might indicate that we are observing a second order
11
O
11
HN
O
NH
O
O
H2, Pd(OH)2/C
HN
15
O
O
N
N
O
N
NH
11
O
N
N
O
11
16 R = H
82%
OR
dansyl chloride
refluxing THF, 35 h
48%
1-naphtoyl chloride
refluxing THF, 18 h
33%
17 R = 1-naphtoyl
Scheme 2.
18 R = dansyl

1704
S. Cicchi et al. / Tetrahedron Letters 49 (2008) 1701–1705
some of the gelating properties of 15 and possesses a free
hydroxyl functionality that can be used as a versatile linker
for attaching new molecular fragments. To demonstrate
this possibility we synthesized the two esters 1713 and 18
(Scheme 2).
Unexpectedly, the synthesis of compounds 17 and 18
required refluxing THF for several hours for completion
and the yields resulted were affected by this reaction
conditions.
Compound 18 revealed that it was unable to form gel in
any solvent tested while compound 17 revealed that it was
an efficient gelator able to gel cyclohexane down to a crit-
ical concentration of 1 mg/mL (Table 1). A clear demon-
stration of the stability of the cyclohexane gel of 17 was
offered by the circular dichroism (CD) spectra registered
at different temperatures that revealed the persistence of
the Cotton effect up to 55 °C (Fig. 4). The presence of
CD effect is peculiar of the gel state,14 since in solution
compound 17 is CD silent, in analogy with what already
observed for compound 2.6a
The arrangement of substituted pyrrolidine units around
a central scaffold revealed a useful approach to the synthe-
sis of an efficient organogelator. This result was not pre-
dictable as demonstrated by the failure represented by the
antracendicarboxylic acid derivative 9. Compound 15
revealed to gel several different apolar and polar solvents
with a remarkable value of critical concentration and
Tgel–sol. The main goal of this work was the production
of a versatile scaffold for further substitution with other
molecular fragments. On this aspect compound 16 gave
some contradictory results: the derivatization with a simple
ester to afford compound 17 gave a good gelator while the
correspondent sulphonate 18 failed to form any gel. Our
actual effort is aimed to the development of this synthetic
approach varying the nature and the length of the side
arm while preserving the two gelating pyrrolidine units.
Nevertheless we also plan to verify the versatility of this
methodology using other gelating units described in the
literature.
Although it cannot be a quantitative observation it is
worthwhile to note the remarkable difference of the specific
Acknowledgments
25
rotatory power ð½aꢁD Þ in solution and in the gel state (Table
The authors acknowledge MIUR for financial support
(FIRB—RBNE033KMA) and CSGI. Brunella Innocenti
and Maurizio Passaponti are acknowledged for technical
assistance.
2). The time required to obtain the formation of a stable,
completely transparent, gel in cyclohexane (around
30 min) also allowed for the measurement of the specific
rotatory power in cyclohexane solution. These data suggest
that during the formation of the self-assembled fibrillar
networks new chiral aggregates are formed, which are
responsible of the specific rotatory power variations.
References and notes
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Shirakawa, M.; Kawano, S.; Fujita, N.; Shinkai, S. Angew. Chem.,
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17 1mg/ml cyclohexane
50
0
30 ˚C
(45 ˚C)
(55 ˚C)
-50
200
250
300
350
400
nm
3. Molecular Gels: Materials with Self-Assembled Fibrillar Networks;
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Diaz, D. D.; Finn; M. G.; Fokin, V. V. PCT Int. Appl. 2007, WO
2007027493, CAN 146:317723.
Fig. 4. CD spectra of compound 17 at different temperatures.
Table 2
Specific rotator power values for 15 and 17
5. Kamikawa, Y.; Kato, T. Langmuir 2007, 23, 274.
6. (a) Cicchi, S.; Ghini, G.; Lascialfari, L.; Brandi, A.; Betti, F.; Berti,
D.; Ferrati, S.; Baglioni, P. Chem. Commun. 2007, 1424; (b) Cicchi, S.;
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7. (a) Afonso, C. A. M.; Lourenco, N. M. T.; Rosatella, A. D. A.
Molecules 2006, 11, 81–102; (b) Mason, P. V.; Champness, N. R.;
25
25
Condition
½aꢁD 15
½aꢁD 17
CH2Cl2 solution, c 0.1
Cyclohexane solution, c 0.1
Cyclohexane gel, c 0.1
ꢀ3.2
ꢀ6
+67
+235
+576
+113

S. Cicchi et al. / Tetrahedron Letters 49 (2008) 1701–1705
1705
Collison, S. R.; Fisher, M. G.; Goetzki, G. Eur. J. Org. Chem. 2006,
1444; (c) Montalbetti, C. A.; Coulter, T. S.; Uddin, M. K.; Reigner, S.
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12. Raghavan, S. R.; Cipriano, B. H. Gel Formation: Phase diagrams
using Tabletop Rheology and Calorimetry. In Molecular Gels:
Materials with Self-Assembled Fibrillar Networks; Weiss, R. G.,
Terech, P., Eds.; Springer: Dordrecht, 2006; pp 241–252.
25
8. Sirkecioglu, O.; Karliga, B.; Talinli, N. Tetrahedron Lett. 2003, 44,
8483.
13. Compound 17: mp = 153–155 °C; ½aꢁD ꢀ6 (c 0.1, CH2Cl2), kabs max
(THF) = 295 nm; kem max (THF, ex 295 nm) = 357 nm; kabs max (cyclo-
hexane gel fase) = 313 nm; kem max (cyclohexane gel fase, ex
295 nm) = 368 nm. 1H NMR (200 MHz; CDCl3) d = 0.87 (12H, t,
CH3), 1.39–1.10 (65H, m, aliphatic chains), 1.60–1.39 (15H, m,
aliphatic chains), 3.23–3.00 (8H, m, CH2NCOO), 3.90–3.64 (8H, br s,
CH2N pyrrolidine), 4.78–4.61 (4H, br s, CH2O ethyle), 4.88–4.78 (4H,
m, NH), 5.23–5.08 (4H, br s, HCO pyrrolidine), 7.62–7.40 (3H,
m, naphthyl), 7.86 (1H, d, J = 7.2 Hz, naphthyl), 8.02 (1H, d,
J = 8.0 Hz, naphthyl), 8.21 (1H, d, J = 7.2 Hz, naphthyl), 8.92 (1H,
d, J = 8.4, naphthyl). 13C NMR (50 MHz; CDCl3) d = 169.8 (2C, s,
triazine), 167.2 (s, C@O naphthyl), 164.4 (s, triazine), 154.8 (4C, s,
C@O), 133.7 (s), 133.3 (d), 131.3 (d), 130.6 (d), 128.4 (d), 127.7 (d),
126.7 (d), 126.1 (d), 125.8 (s), 124.4 (s), 75.0 (4C, d, HCO pyrrolidine),
64.3 (t, CH2O ethyl), 63.2 (t, CH2O ethyl), 50.5 (t, CH2N pyrrolidine),
50.3 (CH2N pyrrolidine), 41.2 (CH2N chains), 31.9, 30.3, 29.8, 29.6,
29.5, 29.3, 26.8, 22.7, 14.1; MS(ESI): m/z 1365.0 (M+Na+, 100%),
25
9. Compound 15: ½aꢁD ꢀ3.2 (c 0.1, CH2Cl2). 1H NMR (200 MHz;
CDCl3) d = 0.97–0.78 (12H, t, CH3), 1.40–1.10 (68H, m, aliphatic
chains), 1.60–1.40 (12H, m, aliphatic chains), 3.23–3.00 (8H, m,
CH2NC(O)O), 3.90–3.65 (10H, m, CH2 pyrrolidine ring, CH2O
ethyl), 4.52–4.41 (2H, m, CH2O ethyl), 4.56 (2H, s, OCH2Ph), 4.86–
4.69 (4H, m, NH), 5.20–5.08 (4H, br s, HCO pyrrolidine), 7.40–7.28
(5H, br s, Ph). 13C NMR (50 MHz; CDCl3) d = 169.8 (2C,s, triazine),
164.3 (s, triazine), 154.8 (4C, s, C@O), 138.0 (s), 128.2 (d), 127.6 (d),
127.5 (d), 75.0 (4C, d, CHO pyrrolidine), 73.1 (t, OCH2Ph), 68.1 (t,
CH2O ethyl), 65.5 (t, CH2O ethyl), 50.5 (2C, t, CH2N pyrrolidine),
50.3 (2C, CH2N pyrrolidine), 41.1 (4C, t, CH2N aliphatic chains),
31.9, 29.8, 29.6, 29.3, 29.2, 26.7, 22.7, 14.1; MS (ESI) m/z 1301
(M+Na+, 100%), 1279.09 (M++1, 58). Elem. Anal. Calcd for
C72H127N9O10: C, 67.62; H, 10.01; N, 9.86. Found C, 67.53; H,
10.22; N, 9.65.
10. Malik, S.; Kawano, S. I.; Fujita, N.; Shinkai, S. Tetrahedron 2007, 63,
7326.
1342.9 (M++1, 36), 1171.9 (78). Elem. Anal. Calcd for C76H127N9O11
C, 67.97; H, 9.53; N, 9.39. Found C, 67.70; H, 9.32; N, 9.28.
:
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