Exceptionally small supramolecular hydrogelators based on aromatic-aromatic interactions

Article abstract of DOI:10.3762/bjoc.7.23

We report herein the use of an aromatic-aromatic interaction to produce small molecule hydrogelators that self-assemble in water and form molecular nanofibers in the resulting hydrogels. Among these hydrogelators, a hydrogelator (6) made from a phenyl-alanine and a cinnamoyl group represents the lowest molecular weight (MW = 295.33 g/mol) peptide-based hydrogelator prepared to date. The supramolecular hydrogels were characterized by transmission electron micrograph (TEM) and fluorescence spec-troscopy, and the results obtained by both techniques correlate well with their rheological properties. Notably, compound 6 can undergo cis/trans-isomerization upon UV irradiation.

Full text of DOI:10.3762/bjoc.7.23

Exceptionally small supramolecular hydrogelators
based on aromatic–aromatic interactions
Junfeng Shi1, Yuan Gao1, Zhimou Yang2 and Bing Xu*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 167–172.
1Department of Chemistry, Brandeis University, 415 South Street,
Waltham, Massachusetts 02453 and 2The Key Laboratory of
Bioactive Materials, Ministry of Education, College of Life Science,
NanKai University, Tianjin 300071, People’s Republic of China
doi:10.3762/bjoc.7.23
Received: 08 November 2010
Accepted: 07 January 2011
Published: 07 February 2011
Email:
Bing Xu* - bxu@brandeis.edu
Guest Editor: J.-P. Desvergne
* Corresponding author
© 2011 Shi et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aromatic–aromatic interaction; cinnamoyl; hydrogel; hydrogelator;
supramolecular
Abstract
We report herein the use of an aromatic–aromatic interaction to produce small molecule hydrogelators that self-assemble in water
and form molecular nanofibers in the resulting hydrogels. Among these hydrogelators, a hydrogelator (6) made from a phenyl-
alanine and a cinnamoyl group represents the lowest molecular weight (MW = 295.33 g/mol) peptide-based hydrogelator prepared
to date. The supramolecular hydrogels were characterized by transmission electron micrograph (TEM) and fluorescence spec-
troscopy, and the results obtained by both techniques correlate well with their rheological properties. Notably, compound 6 can
undergo cis/trans-isomerization upon UV irradiation.
Introduction
Gels formed by three-dimensional, elastic networks to encapsu- molecular weight hydrogelators [24-29]. Despite the intensive
late a liquid [1], have many useful properties (e.g., response to research and rapid advances in the design and synthesis of low
external stimuli and flow in response to shear force [2]) and molecular weight hydrogelators, the minimum structural
applications in several areas (e.g., bioanalysis [3,4], chemical requirement for a small molecule to act as a hydrogelator
sensing [5-7], food processing [8], cosmetics [9], drug delivery to form supramolecular hydrogels has been less explored.
[10,11], and tissue engineering [12,13]). Inspired by the existing We have shown that aromatic–aromatic interactions induce the
and potential applications of gel materials, research on supra- self-assembly of glycopeptides [30] or pentapeptidic deriva-
molecular gels [14-19] has rapidly expanded. Amongst these, tives [31] in water to form nanofibers and supramolecular
self-assembled oligopeptides [20-23], which self-assemble in hydrogels. These results, together with the supramolecular
water to form nanofibers and provide hydrogels for biomedical hydrogelators made from dipeptide conjugates with fluorenyl or
applications, have stimulated the recent research efforts on low naphthyl groups, clearly support the simple notion that
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Beilstein J. Org. Chem. 2011, 7, 167–172.
aromatic–aromatic interactions in water may direct the forma- molecules in water and this may offer insights to address side
tion of hydrogen bonding and would be useful for the supra- effects, polymorphrism, and efficacy of drug candidates that
molecular self-assembly of small molecules in water.
share common molecular features with these hydrogelators.
However, despite the progress noted above, an important ques- Results and Discussion
tion still remains to be answered: What is the minimal set of Scheme 1 shows the structures of the phenylalanines investi-
aromatic–aromatic interactions and hydrogen bonding for mole- gated in this work. We chose four types of aromatic moiety,
cular self-assembly in water to produce supramolecular fluorenyl, naphthyl, naphthalenoxyl, and cinnamoyl groups, to
nanofibers and hydrogels? About a decade ago, Menger [32] covalently attach to the phenylalanine via a simple amide bond.
and coworkers showed that an aroyl L-cystine derivative, which On treatment with 1N NaOH solution, all the prepared com-
has a molecular weight as low as 448.51 g/mol, can form a pounds dissolve. However, when the pH of the solution is
hydrogel at a concentration as low as 0.2 mM and elucidated the changed from basic to slightly acidic, compounds 1, 3, 4 and 6
molecular structure of the hydrogel based on the crystal struc- form hydrogels. Compared with compound 3, compound 2 fails
ture of the gelator. During that gelation experiment, dimethyl to form a gel due to the conjugation between the carbonyl group
sulfoxide (DMSO) was required in the gel, however, this might and the naphthyl group, which partial reduces the rotational
complicate the accurate assessment of the aromatic–aromatic freedom of the naphthyl group that is necessary for self-
interactions and hydrogen bonding since DMSO is prone to assembly. As shown in Table 1, all gels (gels I, II, III and IV
form hydrogen bonds with hydrogen bond donors. Therefore, it formed by compounds 1, 3, 4 and 6, respectively) are thermally
is necessary to explore small supramolecular hydrogelators for and pH reversible. For example, heating the gel formed by
correlating the molecular structure (e.g., numbers of hydrogen 0.3 wt % of compound 1 in water to 56 °C or changing its pH
bond donors and acceptors and aromatic groups) and the capa- from 6.6 to 9.0 leads to a gel–sol phase transition. The gel
bility of self-assembly without the inclusion of DMSO. forms again after restoring the previous conditions, and this
Recently, Dastidar and Das [33] reported that N-(4-pyridyl)- cycle can be repeated several times.
isonicotinamide (MW = 199.21 g/mol) can act as a non-poly-
meric hydrogelator at the concentration of 0.37 wt %, which
Table 1: Typical conditions for the hydrogelation of the phenylalanine
further suggests the possibility of peptide-based hydrogelators
that are smaller than the aroyl L-cystine noted above.
derivatives.
Gel# Compound Conc.
(wt %)a
pHb Temp.
γ0
G0
(Pa)d
(°C)b (%)c
Here, we reported the systematic synthesis and examination of a
series of phenylalanine derivatives and the identification of the
lowest molecular weight peptide-based hydrogelator (MW =
295.33 g/mol) produced to date. Since phenylalanine deriva-
tives belong to a class of insulin absorption promoters [34], this
work not only provides a possible benchmark for low-molec-
ular weight hydrogelators, but also a simple system to help in
understanding the self-assembly of these phenylalanine based
I
1
3
4
6
0.3
0.5
0.7
1.0
6.6
5.7
5.9
4.6
55
45
48
41
0.20 50199
II
0.26
0.56
0.85
4849
7820
2519
III
VI
aThe minimum concentration of the gelator needed for gelation, bthe
gel–sol phase transition pH/temperature at concentration of 1.0%,
ccritical strain [35], delastic constant.
Scheme 1: The chemical structures of the phenylalanine derivatives.
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Beilstein J. Org. Chem. 2011, 7, 167–172.
We noted that the gel IV exists in two phases (Figure 1B) when 6 in these phenylalanine derivatives because solutions of the
it was irradiated by 254 nm UV light for 2 hours: One phase other compounds on acidification change directly to either gels
appears solid like, whilst the other phase flows. Two layers of or suspensions, and the suspensions are unable to become gels
gels are formed after 2 hours aging (Figure 1C). In order to spontaneously. This interesting gelation process suggests that
understand the reason for phase separation, compound 6 was the reversible cis/trans-isomerization provides an additional
placed in a UV reactor for the same duration. As revealed by pathway for rearranging the supramolecular structures and
the 1H NMR (Figure 1F), a new set of peaks at 5.9 ppm and achieving ordered supramolecular structures to produce well-
6.6 ppm appears after UV irradiation, indicating that cis-6 dispersed nanofibers as the matrices of the hydrogels. The fact
forms upon the photo-excitation [36]. Since there was no new that compound 6 has the lowest molecular weight amongst the
peak in the range of 2.5 to 2.9 ppm (Figure S1, Supporting peptide-based hydrogelators suggests that a single amino acid
Information File 1), photopolymerization or photodimerization molecule is unlikely to be able to provide an adequate amount
are unlikely. Furthermore, the result shown in Figure S2 of supramolecular interactions to form nanofibers, entrap the
(Supporting Information File S2) also supports the contention solvent, and result in hydrogelation. Apparently, the cinnamoyl
that heating is insufficient to cause conversion of the trans-
isomer to the cis-isomer during UV irradiation. Thus, we infer
that the formation of two layers in the gel IV after UV irradi-
ation originates from geometric (cis/trans-) isomerism.
Compound 6 also exhibits another interesting phenomenon. On
acidification by 1N HCl solution, the solution of 6 (Figure 2A,
2.0 wt %) first turns from a clear solution into a suspension
(Figure 2B). The suspension becomes an opaque gel
(Figure 2C) when the pH reaches 4.6, which finally turns into a
Figure 2: The optical images of (A) solution of 6 (2 wt %, pH = 9.0),
(B) suspension of 6 (2 wt %, pH = 6.5), (C) opaque gel of 6 (2 wt %,
clear hydrogel after aging for ten days (Figure 2D): The aging
pH = 4.6), (D) transparent gel of 6 (2 wt %, pH = 4.6, aging for 10
days).
process apparently helps the small molecules of 6 to disperse
evenly and self-assemble again. This behavior seems unique to
Figure 1: Optical images of (A) gel IV (1.5 wt %, pH = 4.6), (B) gel IV after UV irradiation (no aging), (C) gel IV after UV irradiation (aging 2 hours), (D)
the structure of compound 6 in trans- and cis-isomers, (E) the NMR spectra of compound 6 before and (F) after UV irradiation for 2 hours.
169

Beilstein J. Org. Chem. 2011, 7, 167–172.
group is the minimum structure motif to provide sufficient
aromatic–aromatic interactions for a phenylalanine derivative to
act as a hydrogelator.
Figure 3 shows the frequency dependence of storage modulus
(G’) and loss modulus (G’’) for gels I to IV at a concentration
of 1.0 wt %. The values of the dynamic storage moduli (G’) of
all gels are higher than those of their dynamic loss moduli (G”),
indicating that all samples behave as viscoelastic materials. The
values of G’ of the hydrogels exhibit little dependence on the
frequency (from 0.1 to 200 rad/s), suggesting that the matrices
of gels have good tolerance to external shear force. Gel IV,
which formed by the lowest molecular weight hydrogelator
among the phenylalanine derivatives prepared, has the lowest
storage modulus. Gel I, which was formed by a hydrogelator
with the highest molecular weight among compounds 1–6,
exhibits the strongest mechanical strength among the gels
reported in this work. This is in agreement with the fact that the
interactions between fluorenyl and phenyl groups are stronger
than the interactions among phenyl groups. Figure 3B shows the
modulus (G’ and G’’)-strain profiles of gels I to IV, which
provide the maximum G’ values in the linear region and values
of critical strain. The G’ remained almost constant when the
strain increased and then suddenly decreased, indicating the loss
of crosslinking within the gel network. Obviously, the critical
strain of gel IV is greater than the others. These results suggest
that gel IV can form a more complex network structure, which
agrees with the morphology as revealed by TEM (Figure 4).
Figure 4 shows the TEM images of the matrices of gels I to IV.
The phenylalanine based hydrogelator self-assemble into
nanofibers that physically cross-link to form a fibrous network
as the matrix of hydrogel. For example, the fibers in gel III
(Figure 4C) are longer and larger than those in gel II
(Figure 4B), agreeing with the fact that gel III has a larger criti-
cal strain and higher storage modulus. In the TEM image of gel
IV (Figure 4D), the fibers are smaller and longer than other
gels, which could contribute to its relative high critical strain
and low storage module values. Unlike other gels, nanoparti-
cles (20–80 nm) string together to constitute the matrices for gel
I, indicating a high tendency for aggregation. This result also
supports the fact that the fluorenyl and phenyl groups have the
strongest interactions among those hydrogelators and result in
the highest storage moduli among the gels I–IV.
Figure 3: (A) Frequency dependence of dynamic storage modulus (G’)
and loss modulus (G”) of gels I to IV at 1.0 wt % concentration. (B)
Dynamic storage modulus (G’) and loss modulus (G’’) versus strain for
the gels I to IV.
Based on emission spectra of the hydrogels (Figure 5),
aromatic–aromatic interactions increase in the gel state, evi-
denced by the fact that most of bands in the gel phase show red
shift. In gel I, the band centers at about 309 nm in solution and
shift to about 329 nm in the gel phase, suggesting that Fmoc
group overlaps with the phenyl group; the shoulder at 363 nm
Figure 4: TEM images of the nanofibers that act as the matrices of gel
I (A), gel II (B), gel III (C) and gel IV (D).
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Beilstein J. Org. Chem. 2011, 7, 167–172.
likely originates from the antiparallel dimerization of the fluo- Acknowledgements
renyl group whilst the small broad bands above 400 nm appar- This work was partially supported by start-up funds from Bran-
ently relate to trimeric or tetrameric aggregates of the Fmoc deis University and National Institute of Health. Junfeng Shi
groups. In gel II and gel III, the red shifts are smaller than that thanks the Scholarship from Chinese Scholarship Council
of gel I (from 332 to 333 nm in gel II, from 345 to 360 nm in (2008638092).
gel III), suggesting that the interactions between naphthyl
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