Gelation behavior of 2H-Chromene N-acylamino acid conjugates

Article abstract of DOI:10.1021/jo900066m

2H-Chromene-based conjugates of N-acyl-1,Ω-amino acids (5, 9a-f, 14a-f) of natural amino acids (10a,b) and of dipeptide (10c) are prepared (60-97%) by N-acylbenzotriazole methodology in aqueous media at 20 °C. Gelation properties of the corresponding sodi

Full text of DOI:10.1021/jo900066m

Gelation Behavior of 2H-Chromene N-Acylamino Acid Conjugates
Alan R. Katritzky,* Rajeev Sakhuja, Levan Khelashvili, and Karem Shanab
Center for Heterocyclic Compounds, Department of Chemistry, UniVersity of Florida,
GainesVille, Florida 32611-7200
katritzky@chem.ufl.edu
ReceiVed January 12, 2009
2H-Chromene-based conjugates of N-acyl-1,ω-amino acids (5, 9a-f, 14a-f) of natural amino acids (10a,b)
and of dipeptide (10c) are prepared (60-97%) by N-acylbenzotriazole methodology in aqueous media at
20 °C. Gelation properties of the corresponding sodium salts in DMF and DMSO are generalized with
respect to an increase or decrease in the chain length of the spacer.
Introduction
dispersed in organic solvents.6 “Smart gels” (i.e., gels whose
properties can be controlled reversibly or irreversibly in response
to changes in external chemical, photochemical, thermal, or
sonic stimuli) are organogelator materials of particular interest.7-9
Thermoreversible physical gels generated from relatively low
molecular mass organic molecules represent a new class of self-
assembling organic materials of potential interest as nanostruc-
tured materials and devices.10-13 Control of the gelation process
by external stimuli through addressable functions introduced
into the supramolecular units (for example, organic photo-
chromes) could allow light to modify the self-assembly process
of individual molecules and the resulting supramolecular
Gels are an example of nanoscale functional materials for
which various synthetic protocols have been developed. Low
molecular weight amphiphiles can self-assemble into nanoscale
fibers that entangle to form 3D fibrous networks which organize
liquids to solid or semisolid gels.1,2 Supramolecular gels can
form various exotic nanoaggregates such as fibers, thin sheets,
helical and lamellar structures.3 Such gels are used in templated
materials4 for drug delivery, cosmetics, separations, and bio-
mimetics.5 Supramolecular gel formation occurs when various
structurally diverse low molecular weight organic molecules
involving amidic, carbamate, urea, or oxalamide groups and long
aliphatic chains or aromatic groups with a large surface are
(6) Fages, F.; Voegtle, F.; Zinic, M. Top. Curr. Chem. 2005, 256, 77–131.
(7) Wang, S.; Shen, W.; Feng, Y.; Tian, H. Chem. Commun. 2006, 1497–
1499.
* To whom correspondence should be addressed. Phone: (352) 392-0554.
Fax: (352)-392-9199.
(1) Menger, F. M.; Zhang, H.; Caran, K. L.; Seredyuk, V. A.; Apkarian,
R. P. J. Am. Chem. Soc. 2002, 124, 1140–1141.
(2) John, G.; Jung, J. H.; Masuda, M.; Shimizu, T. Langmuir 2004, 20, 2060–
2065.
(8) Kawano, S.; Fujita, N.; Shinkai, S. J. Am. Chem. Soc. 2004, 126, 8592–
8593.
(9) Kawano, S.; Fujita, N.; Shinkai, S. Chem.sEur. J. 2005, 11, 4735–4742.
(10) Suzuki, M.; Nigawara, T.; Yumoto, M.; Kimura, M.; Shirai, H.;
Hanabusa, K. Org. Biomol. Chem. 2003, 1, 4124–4131.
(11) Ahmed, S. A.; Sallenave, X.; Fages, F.; Mieden-Gundert, G.; Mueller,
W. M.; Mueller, U.; Voegtle, F.; Pozzo, J.-L. Langmuir 2002, 18, 7096–7101.
(12) Van Esch, J. H.; Feringa, B. L. Angew. Chem., Int. Ed. 2000, 39, 2263–
2266.
(3) Terech, P.; Weiss, R. G. Chem. ReV. 1997, 97, 3133–3159.
(4) Xue, P.; Lu, R.; Huang, Y.; Jin, M.; Tan, C.; Bao, C.; Wang, Z.; Zhao,
Y. Langmuir 2004, 20, 6470–6475.
(5) Vemula, P. K.; John, G. Chem. Commun. 2006, 2218–2220.
(13) Bouas-Laurent, H.; Durr, H. Pure Appl. Chem. 2001, 73, 639–665.
3062 J. Org. Chem. 2009, 74, 3062–3065
10.1021/jo900066m CCC: $40.75 2009 American Chemical Society
Published on Web 03/18/2009

2H-Chromene N-Acylamino Acid Conjugates
SCHEME 1
network.11 Spiropyrans, spirooxazines, naphthopyrans, dia-
rylethenes, and azobenzenes are all photochromic systems that
display two molecular states with different absorption spectra.11,13
Interestingly, light-induced transformation can cause reversibly
important structural and physicochemical changes as depicted
in 2H-chromene13 (Figure 1).
gelation of chromene-2H-ω-amino acids conjugates and the
corresponding natural amino acid analogues has appeared.
Herein we report an efficient N-acylbenzotriazole-mediated
preparation of 2H-chromene-based N-acyl-1,ω-amino acid (5,
9a-f, 14a-f) and natural amino acids and dipeptide (10a-c)
conjugates with 60-97% yields in aqueous media at 20 °C, in
order to investigate the trends in the gelation properties of the
sodium salts of these chromene-2H natural and ω-amino acid
conjugates in DMF and DMSO with chain length.
Results and Discussion
3,3-Diphenyl-3H-benzo[f]chromene-8-carboxylic acid (3) was
prepared from 6-hydroxynaphthalene-2-carboxylic acid (6) and
1,1-diphenylprop-2-ynol (7): modifying the literature,11 the
cyclization was accomplished in toluene using a Dean-Stark
trap during 6-8 h, and the product was recrystallized from
acetonitrile, thus avoiding chromatography. Carboxylic acid (3)
was converted into N-acylbenzotriazole derivative 8 (89%)
following our published procedure.19 N-Acylbenzotriazole (8)
was coupled with various natural and ω-amino acids in aqueous
THF/triethylamine at 20 °C for 4-10 h. Our approach allows
the use of unprotected natural and ω-amino acids and provides
yields of 60-97% (Scheme 2 and Table 1).
3,3-Diphenyl-3H-benzo[f]chromene-7-carboxylic acid (12)
was prepared similarly (74%) from 6-hydroxynaphthalene-1-
carboxylic acid (11) and 1,1-diphenylprop-2-ynol (7). Acid 12
was converted into the N-acylbenzotriazole derivative 13 (72%),
which was also coupled with various ω-amino acids to give
the corresponding 7-substituted 2H-chromene amino acid con-
jugates 14a-f (Scheme 3 and Table 2).
The gelation behaviors of the sodium salts of 9a-f, 5, 10a-c,
and 14a-f were investigated in DMF and DMSO with a
concentration of 2 and 5 wt%/v via the inverted test tube
method20 (Table 3).
Thus we demonstrated that incorporation of ω-amino acids
to 2H-chromene 8-carboxylic derivative with chain lengths of
11 and 12 (5 and 9f) strongly gelates (noted as G) in DMF and
DMSO as the gels formed by them upon cooling are stable at
room temperature for months. The conjugates with chain lengths
of 6, 7, and 8 (9c, 9d, and 9e) gelatinized DMF at low
FIGURE 1. Photochromism in chromenes.
Ahmed et al. recently reported organogelators based on 2H-
chromene and N-acyl-1,ω-amino acids that induce gelation of
organic fluids such as DMF or DMSO,11,14 demonstrating that
while incorporation of a photoresponsive unit into the sodium
N-acyl-11-aminoundecanoate scaffold does not suppress its
gelation ability, the formation of supramolecular aggregates by
intermolecular hydrogen bonds is strongly affected by photo-
induced structural changes of the photochromic subunit. Such
multiaddressable self-assembling organogelators are potential
building blocks for the development of functional materials and
devices. The methyl ester 4 of 2H-chromene-8-carbonyl amino
acid was previously prepared11 (22%) from 3,3-diphenyl-3H-
benzo[f]chromene-8-carboxylic acid (3) and methyl 11-ami-
noundecanoate hydrochloride by coupling with DCC/DMAP
followed by alkaline hydrolysis of 4 to give the expected
chromene-2H amino acid conjugate (5, 46%; Scheme 1), but
this methodology required anhydrous reaction conditions and
tedious workup.11
The gelation abilities of N-acyl-1,ω-amino acids conjugate
in organic solvents,15 and the formation of fibrous molecular
assemblies and gels from N-acyl derivatives of natural amino
acids such as alanine or aspartic acid have also been studied.16-18
However, no generalization of the effect of chain length on the
(14) Vollmer, M. S.; Clark, T. D.; Steinem, C.; Ghadiri, M. R. Angew.Chem.,
Int. Ed. 1999, 38, 1598–1601.
(15) Mieden-Gundert, G.; Klein, L.; Fischer, M.; Voegtle, F.; Heuze, K.;
Pozzo, J.-L.; Vallier, M.; Fages, F. Angew. Chem., Int. Ed. 2001, 40, 3164–
3166.
(16) Bhuniya, S.; Park, S. M.; Kim, B. H. Org. Lett. 2005, 7, 1741–1744.
(17) Imae, T.; Takahashi, Y.; Muramatsu, H. J. Am. Chem. Soc. 1992, 114,
3414–3419.
(19) (a) Katritzky, A. R.; Suzuki, K.; Singh, S. K. Synthesis 2004, 2645–
2652. (b) Katritzky, A. R.; Khelashvili, L.; Munawar, M. A. J. Org. Chem. 2008,
73, 9171–9173.
(20) Murata, K.; Aoki, M.; Suzuki, T.; Harada, T.; Kawabata, H.; Komori,
T.; Ohseto, F.; Ueda, K.; Shinkai, S. J. Am. Chem. Soc. 1994, 116, 6664–6676.
(18) Bhattacharya, S.; Krishan-Ghosh, Y. Chem. Commun. 2001, 185–186.
J. Org. Chem. Vol. 74, No. 8, 2009 3063

Katritzky et al.
SCHEME 2
SCHEME 3
TABLE 2. Preparation of 2H-Chromene Amino Acid Conjugates
(14a-f)
TABLE 1. Preparation of 2H-Chromene Amino Acid Conjugates
(9a-f, 5, and 10a-c)
entry time (h) target compounds yield (%) mp ((°C) decomp.)
entry time (h) target compounds yield (%) mp (lit. mp (°C) decomp.)
1
2
3
4
5
6
8
10
8
8
8
14a
14b
14c
14d
14e
14f
86
83
72
79
86
71
99-101
114-116
207-209
146-148
85-87
1
2
3
4
5
6
7
8
9
10
6
6
5
4
4
5
3
7
5
6
9a
9b
9c
9d
9e
5
9f
10a
10b
10c
81
85
66
97
91
60
62
91
82
92
212-213
216-218
195-197
176-178
202-204
145-146(147)
121-122
198.5-200.5
147-148
110-112
8
86-88
temperature, but the gels formed are not stable at room
temperature and hence are noted as Gs. Their corresponding
solutions in DMSO are clear (noted as S) and hence classified
3064 J. Org. Chem. Vol. 74, No. 8, 2009

2H-Chromene N-Acylamino Acid Conjugates
TABLE 3. Gelation Properties of the Sodium Salt of
2H-Chromene Amino Acid Conjugate (Na-9a-f, Na-5, Na-10a-c,
Na-14a-f)a
dropwise thionyl chloride (0.59 g, 4.92 mmol). After 2 h stirring
at room temperature, 3,3-diphenyl-3H-benzo[f]chromene-8-car-
boxylic acid (3) (1.55 g, 4.10 mmol) was added and the mixture
was stirred for an additional hour. The precipitate was filtrered and
the organic filtrate diluted with CH2Cl2 (20 mL) and washed with
saturated Na2CO3 solution (20 mL × 3). The organic layer was
separated, dried over magnesium sulfate, and concentrated in
vacuum to afford a yellow solid, which was recrystallized from
DCM/hexane to give pure product as 1.74 g (89%) of yellow
crystals: mp 206-207 °C (decomp.); 1H NMR (CDCl3) δ 6.33 (d,
J ) 9.9 Hz, 1H), 7.25-7.37 (m, 8H), 7.47-7.50 (m, 4H), 7.54 (t,
1H), 7.70 (t, 1H), 7.84 (d, J ) 8.7 Hz, 1H), 8.09 (d, J ) 9.0 Hz,
1H), 8.16-8.22 (m, 2H), 8.40 (d, J ) 8.4 Hz, 1H), 8.75 (d, J )
1.2 Hz, 1H); 13C NMR (CDCl3) δ 83.2, 114.0, 114.8, 118.9, 119.6,
120.1, 121.7, 126.1, 126.2, 127.0, 127.6, 127.7, 128.0, 128.2, 128.3,
130.3, 131.9, 132.4, 132.5, 135.1, 144.4, 145.7, 153.3, 166.4. Anal.
Calcd for C32H21N3O2: C, 80.15; H, 4.41; N, 8.76. Found: C, 79.90;
H, 4.33; N, 8.79.
compound
DMF
DMSO
compound
DMF
DMSO
9a
9b
9c
9d
9e
5
I
S
S
S
S
S
Gs
G
G
S
10b
10c
14a
14b
14c
14d
14e
14f
S
Gs
I
S
S
S
S
Gs
Gs
Gs
G
G
S
S
Gs
Gs
Gs
Gs
S
Gs
Gs
Gs
9f
10a
a G ) Gel formed when cooled at 2-20°C and stable at room
temperature. Gs Gel formed but turned into solution at room
temperature. Gel not formed, compound soluble at rt.
compound insoluble even on heating.
)
)
S
I )
as nongelators with respect to DMSO. With further decrease in
the chain length to 4 and 5 (9a and 9b), the gelation ability is
completely eliminated in both DMF and DMSO. The same trend
in the gelation behavior was not observed for the new 2H-
chromene 7-carboxylic derivative with varying the chain lengths
from 5 to 12 (14a-f). The derivatives with C-7, C-8, C-11,
and C-12 chains (14c-f) partially gelatinized DMF and DMSO
only at low temperatures, while the derivatives with C-5 and
C-6 chains (14a,b) are nongelators in either of the two solvents.
Our studies also showed that the natural amino acid 2H-
chromene conjugates (10a,b) are nongelators, while the dipep-
tide 2H-chromene glycyl-DL-alanine conjugate (10c) gelatinized
DMF only at low temperature, but not DMSO, and thus is noted
as Gs. Although the chain length in this dipeptide is small, the
presence of two peptide bonds may account for its partial
gelation behavior.
General Procedure for Preparation of 2H-Chromene Amino
Acid Conjugates (5, 9a-f, 10a-c, 14a-f). A mixture of (1H-
benzo[d][1,2,3]triazol-1-yl)(3,3-diphenyl-3H-benzo[f]chromen-8-
yl)methanone (8 or 13) (1 equiv) and amino acid (1 equiv) was
dissolved in THF/H2O (10 mL, 6 + 4). After addition of
triethylamine (2 equiv), the reaction was stirred for 4-10 h. The
course of the reaction was monitored by TLC (MeOH/DCM, 2:98).
For workup, THF was removed under reduced pressure and 4 N
HCl was added dropwise to yield a precipitate which was filtered
and washed with water to furnish excellent yields of the desired
compounds. Pure products were obtained by recrystallization from
THF/H2O or acetonitrile.
6-(3,3-Diphenyl-3H-benzo[f]chromene-8-carboxamido)hexano-
ic acid (9c): 1H NMR (DMSO-d6) δ 1.32-1.35 (m, 2H), 1.54 (br
s, 4H), 2.21 (t, J ) 7.2 Hz, 2H), 3.29 (m, 2H), 6.63 (d, J ) 9.9 Hz,
1H), 7.24-7.29 (m, 2H), 7.33-7.39 (m, 5H), 7.49-7.54 (m, 5H),
7.91 (t, J ) 9.0 Hz, 2H), 8.17 (d, J ) 9.0 Hz, 1H), 8.35 (s, 1H),
8.57 (m, 1H); 13C NMR (DMSO-d6) δ 24.2, 26.0, 28.8, 33.5, 81.6,
113.8, 118.8, 119.1, 121.6, 125.0, 126.2, 127.4, 128.0, 128.1, 128.5,
129.8, 130.3, 130.9, 144.5, 151.0, 165.7, 174.4. Anal. Calcd for
C32H29NO4: C, 78.19; H, 5.95; N, 2.85. Found: C, 77.99; H, 6.00;
N, 3.00.
General Procedure for Preparation of Sodium Salts of 2H-
Chromene Amino Acid Conjugates (Na-5, Na-9a-f, Na-10a-c,
Na-14a-f). A mixture of 2H-chromene amino acid conjugates (5,
9a-f, 10a-c, 14a-f) (1 equiv) and 1 N NaOH solution (1.2 equiv)
was stirred in methanol at room temperature for 3-4 h. The solvent
was then removed under vacuum. The product was washed with
diethyl ether (×2) and dried under vacuum to yield fluffy crystalline
solids, which were used as such for the gelation experiments by
the inverted test tube method.20
Gelation Experiments “Inverted Test Tube Method”: In a
typical gelation experiment, a weighed amount of sodium salt of
the chromene amino acid conjugate (Na-5, Na-9a-f, Na-10a-c,
Na-14a-f) and 1 mL or organic solvent (DMF or DMSO) were
placed in a septum-capped sample tube (generally 2 and 5 wt%/v).
The sample tube was heated under agitation until the solid had
dissolved. The solution was cooled in an ice bath and set aside at
25 °C for 6-8 h. The gelation behaviors as G, Gs, S, and I of
these conjugates are summarized in Table 3.
Conclusion
2H-Chromene-based conjugates of N-acyl-1,ω-amino acids,
natural amino acids, and dipeptide were prepared (60-97%)
by benzotriazole methodology in aqueous media at 20 °C, and
the gelation properties of their sodium salts in DMF and DMSO
were generalized with respect to an increase or decrease in the
chain length of the spacer.
Experimental Section
Preparation of 3,3-Diphenyl-3H-benzo[f]chromene-8-carboxy-
lic acid (3). A mixture of 6-hydroxynaphthalene-2-carboxylic acid
(0.94 g, 5 mmol) (6) and 1,1-diphenylpropyn-1-ol (1.04 g, 5 mmol)
(7) was dissolved in dry acetonitrile (150 mL). A catalytic amount
of p-toluenesulfonic acid (100 mg) was added, and the reaction
mixture was stirred for 2 days. The precipitate thus obtained was
filtered; the filtrate was concentrated to half its volume, and newly
precipitated solid was again filtered. The combined solids were
recrystallized from acetonitrile to give 1.36 g (72%) of 3,3-diphenyl-
3H-benzo[f]chromene-8-carboxylic acid (3) as colorless crystals:
1
mp 305-306 °C (decomp.); H NMR (DMSO-d6) δ 6.62 (d, J
)10.2 Hz, 1H), 7.22-7.27 (m, 2H), 7.31-7.41 (m, 5H), 7.47-7.50
(m, 5H), 7.96-8.01 (m, 2H), 8.17 (d, J ) 9.0 Hz, 2H), 8.52 (s,
1H); 13C NMR (DMSO-d6) δ 82.1, 114.0, 119.1, 119.1, 122.0,
126.0, 126.3, 127.6, 128.1, 128.3, 128.7, 131.2, 131.4, 131.6, 144.5,
151.8, 167.4. Anal. Calcd for C26H18O3: C, 82.52; H, 4.79. Found:
C, 82.15; H, 4.80.
Supporting Information Available: Compound character-
ization data for 9a,b, 9d,e, 5, 9f, 10a-c, and 14a-f. Copies of
1H and 13C spectra of 3, 8, 12, 13, 9a-e, 5, 9f, 10a-c, and
14a-f. This material is available free of charge via the Internet
at http://pubs.acs.org.
Preparation of (1H-Benzo[d][1,2,3]triazol-1-yl)(3,3-diphenyl-
3H-benzo[f]chromen-8-yl)methanone (8). To a solution of 1H-
benzotriazole (1.95 g, 16.40 mmol) in CH2Cl2 (20 mL) was added
JO900066M
J. Org. Chem. Vol. 74, No. 8, 2009 3065