An emissive and pH switchable hydrazone-based hydrogel

Article abstract of DOI:10.1039/c5cc03007b

A serendipitous discovery has led to a new hydrazone-based low molecular weight fluorescent super-hydrogelator. The gelation and emission properties can be switched "ON" and "OFF" using pH, enabling the sensing of biogenic amines emanating from spoiled cod.

Full text of DOI:10.1039/c5cc03007b

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COMMUNICATION
An Emissive and pH Switchable Hydrazone-Based Hydrogel
Hai Qian, Ivan Aprahamian*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
composition of the hydrogel. It is no surprise then that smart
5
A serendipitous discovery has led to a new hydrazone-based
low molecular weight fluorescent super-hydrogelator. The
gelation and emission properties can be switched “ON” and
“OFF” using pH, opening the way to the sensing of biogenic
amines emanating from spoiled cod.
45 emitting hydrogels based on simple πꢀsystems are rarely
reported.15 One strategy for addressing this setback is by
developing biꢀfunctional “monomers”: structurally simple
gelators that also function as fluorophores.
The multifaceted hydrazone functional group has been
50 extensively employed in various applications ranging from
sensing to drug development.16 Hydrazones have been employed
in gels as well. For example, hydrazone crosslinked polymeric
hydrogels were used as smart matrixes in tissue engineering,17
and their metal binding ability was employed in the generation of
55 hierarchical 2×2 supramoelcular polymer gels.18 In most reported
cases though, hydrazoneꢀbased gels are polymeric in nature (i.e.,
the hydrazones function as linkers or pendants) and low
molecular weight hydrazoneꢀbased gelators are rare.19 Moreover,
such gels are not emissive in general because common
60 hydrazones require additional modifications to their backbone in
order to become emissive.20 Herein, we report the serendipitous
finding of (to the best of our knowledge) the simplest hydrazoneꢀ
based emitting gelator (1; Scheme 1), which is also one of the
simplest reported π systemꢀcontaining hydrogelators. The critical
65 gel concentration of 1 was measured to be 0.1 wt% making it a
superꢀgelator.21 The formation of the gel can be reversibly
controlled using both temperature and pH. Moreover, the gelation
process controls the emission of the system, turning it “ON” and
“OFF” as a function of gelꢀsol state. To demonstrate the utility of
70 such a biꢀfunctional gelator we developed a simple detector for
biogenic amines emanating from food spoilage.
10 Low molecular weight gelators (LMWGs) are a fascinating
family of smart materials,1 composed of lightꢀweight organic
molecules that selfꢀassemble through nonꢀcovalent interactions,
such as hydrogen bonding, πꢀπ stacking and ionic interactions,
into solvent trapping fibril networks.2 As opposed to crossꢀlinked
15 polymeric gels, such systems can overcome structural
imperfections through the reversibility of their intermolecular
bonds.3 This property and the susceptibility of these bonds to
external stimuli or environmental conditions, have been
extensively employed in the development of gelꢀbased sensors,4
20 adaptive materials,5 and drug delivery systems.6 Another
advantage of LMWGs vs. polymeric gels is that they will have
more predictable degradation profiles in the body thus facilitating
their use in medical applications.7 While numerous LMWGs have
been reported, there are still many challenges associated with
25 designing new families of lowꢀweight gelators, mainly because of
our limited understanding of the gelation process and factors that
lead to it.8
N,N′ꢀDimethylurea is one of the lowest molecular mass
gelators (Mw 88) reported in the literature.9 Hydrogen bonding is
30 the main driving force for gelation in this compound, and in order
to amplify its strength organic solvents are used as the liquid
phase.10 Such organogels are usually not biocompatible limiting
their application in the fields of regenerative medicine, tissue
engineering, enzymatic chemistry, and so forth.11 Hydrogels on
35 the other hand are more compatible with bioꢀapplications;
however, introducing signal transduction12 pathways in such
systems in order to make them amenable to such applications
complicates their synthesis. For example, introducing emission
functionality is a convenient strategy for sensing applications, but
40 this usually requires increasing the size of the πꢀsystem of known
gelators1 or the encapsulation13 of fluorophores in the gel. The
scarcity of hydrogels that consist of aromatic moieties14
obfuscates the former approach, while the latter complicates the
Scheme 1. Chemical structures of gelator 1 and the two control
compounds 2 and 3.
75
Compounds 1, 2 and 3 were obtained from the hydrolysis of
corresponding ethyl esterꢀcontaining hydrazones (see ESI†). The
1
latter were synthesized following published protocols.22 The H
Department of Chemistry, Dartmouth College, Hanover, New Hampshire
03755, USA. E-mail: ivan.aprahamian@dartmouth.edu.
NMR spectrum of 1 shows two extremely downfield proton
signals at
δ = 18.47 and 13.93 ppm (Fig. S2, ESI†), which
†
Electronic supplementary information (ESI) available: General
80 indicate the presence of two hydrogen bonds (Hꢀbonds) in the
molecule. This assumption was further substantiated by the two
information, synthesis, NMR spectra, gelation properties, SEM
characterization, and crystallographic data for compounds 1 and 3. CCDC:
1056712 and 1056713. See DOI: 10.1039/b000000x/
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Hꢀbonds found in the crystal structure of 1 (Fig. 2a); one between
function as an emissive gelator.
the NꢀH proton and the C=O oxygen atom (NꢀH⋅⋅⋅O, 2.5539(4) Å,
133.990(2)°), and the other between the pyridine nitrogen and
OH proton (OꢀH⋅⋅⋅N, 2.5548(4) Å, 137.476(2)°).23 The 2D
ROESY spectrum (Fig. S4, ESI†) of 1 shows ROE correlations
5
between protons H3 and H4, and proton H3 and the signal at
δ =
13.93 ppm. This interaction made us conclude that the latter
signal belongs to the hydrazone NH proton, and that 1
predominantly adopts the Z configuration in solution. This
10 assignment is contrary to all our previous hydrazone switches,
which predominantly adopt the E configuration is solution.24 We
attribute this anomaly to the presence of two intramolecular Hꢀ
bonds in 1, which not only lock it in the Z configuration, but also
contribute to its gelation properties (vide infra).
Fig. 2 Wire drawings of the a) monomer, b) dimer, and c) water
50 containing selfꢀassembled crystal packing of 1. The orange dashes
emphasize the hydrogen bonds and πꢀπ interactions that participate in the
formation of the dimer and aggregates. The hydrogen atoms on the phenyl
and pyridyl rings have been omitted for clarity.
15
To obtain a deeper understating of the gelation mechanism, we
55 further examined the crystal structures of 1 and 3.29 Compound 1,
which has an almost planar geometry (Fig. 2a),30 dimerizes in a
headꢀtoꢀtail fashion through two equivalent intermolecular Hꢀ
bonds formed between the pyridyl ring nitrogen and the OꢀH
hydrogen atom (OꢀH⋅⋅⋅N, 2.8923(4) Å, 133.406(2)°) (Fig. 2b). In
60 the next step of assembly, four such dimers are brought together
through moderate πꢀπ interactions between the pyridyl and
phenyl rings of different dimer units (3.9944(1) Å) (Fig. 2c). This
whole construct is also held together through multiple Hꢀbonds
between the dimer carbonyl oxygen atoms and disordered water
65 chains (Fig. 2c); the following OꢀH⋅⋅⋅O bonds can be detected, (i)
2.7970(2) Å, 122.700(1)°, (ii) 2.7970(2) Å, 98.638(1)°, and (iii)
2.7658(1) Å, 102.884(7)° (Fig. 2c). As for compound 3, the
substitution of the pyridyl ring with a phenyl group leaves only
one Hꢀbond in the system (NꢀH⋅⋅⋅O; Fig. S12, ESI†). This small
70 change completely alters the dimerization of 3 in the solidꢀstate
(Fig. S16, ESI†). The COOH group, which is a known
Fig. 1 Photographs of aqueous solutions of 1, 2, and 3 (0.1 wt%) under a)
ambient light and b) UV light (365 nm).
Commonly, gelation requires the conversion from
a
heterogeneous solution to a homogeneous one upon heating, and
20 then to gel state upon cooling. While hydrazone 1 has low
solubility in cold water, it is highly soluble in hot water (as well
as all common organic solvents except hexanes, Table S1, ESI†).
Upon cooling the solution, a yellow hydrogel is formed (Fig. 1a).
This gelꢀsol transition is reversible and can be cycled multiple
25 times. The critical gel concentration of 1 was measured to be 0.1
wt% (ca. 4.1 mM); the ability to form gels at such a low
concentration (<1 wt%) is recognized as superꢀgelation.21 Inverse
flow measurements25 yielded the gelꢀsol transition temperature of
o
Tgel = 49.5 C, while gels molded into a D shape were stable for
30 almost a day (Fig. S14, ESI†). More interestingly, the hydrogel
itself exhibits strong fluorescent emission under UV (365 nm)
light (Fig. 1b), while it is nonꢀemissive in the sol state (quantum
yield <0.01; Fig. S17, ESI†). We attribute this enhanced emission
of 1 to its rigidification when locked in the 3D gel network (Fig.
35 S20, ESI†).26 We hypothesize that the rotation of the phenyl
group in 1 quenches its emission emanating from excitedꢀstate
intramolecular proton transfer (ESIPT);27 restricting this motion
in the gel reinstates emission leading to the fluorescent hydrogel.
In order to have a better understanding of why 1 forms a gel
40 we studied the gelation properties of hydrazones 2 and 3, which
do not form as many intramolecular Hꢀbonds as 1.28 While
compound 2 is soluble in water (and other organic solvents), 3
forms a suspension (Table S1, ESI†). More importantly, neither
can form a hydrogel (Fig. 1) and their aqueous solutions are nonꢀ
45 emissive under UV light. These results indicate that the two
intramolecular Hꢀbonds are required for the hydrazone to
supramolecular synthon,31 forms
a
dimer through two
complementary intermolecular Hꢀbonds (OꢀH⋅⋅⋅O=C, 2.6509(2) Å,
173.040(4)°) (Fig. S16b, ESI†). The dimerization causes the
75 phenyl groups to point outside and generate a hydrophobic
periphery. Further aggregation of the dimers expands the
hydrophobic outline, which might explain the low water
solubility of 3 compared to 1 and 2 (Fig. S16c, ESI†). Because
the phenyl rings are disordered, no effective πꢀπ interactions can
80 be observed. This loss of πꢀstacking may also contribute to the
nonꢀgelation property of 3. This analysis highlights the
importance of intermolecular Hꢀbonds as well as πꢀπ interactions
in the sequential formation of the dimers, tubular water channels,
and the 3D network in 1. We hypothesize that a similar
85 mechanism can explain its gelation properties.
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biogenic amines.34 These compounds are the products of the
45 metabolism of food, and are associated with food spoilage and
poisoning.35 Cadaverine, putrescine, histamine, and tyramine are
the most prevalent biogenic amines in meat.36 We first checked
the sensitivity of the emissive gel to each one of these amines
(Fig. S21, ESI†). As expected, the gels collapsed in the presence
50 of the biogenic amines (BAs). Next, we let cod meat go bad and
added the obtained solution on top of an emissive gel pad (Fig. 5,
red circles; Fig. S22, ESI†). The gel collapsed and the emission
was quenched only in the regions that came into contact with the
spoiled cod solution. On the other hand, no collapse or quenching
55 was observed when a fresh cod solution or water was added on
top of the gel (Fig. 5, blue and black circles, respectively). We
attribute the difference in behaviour between the solutions to the
increased concentration of BAs in the spoiled cod solution, which
increases its basicity leading to the collapse of the gel. The
60 reversibility of the gelation process opens the door to using this
smart emissive material in the active monitoring of food spoilage.
Fig. 3 (a) Confocal fluorescent and (b) SEM (in H2O mode) images of 0.1
wt% of wet hydrogel.
Further insights into the hydrogel formation were obtained
from scanning electron (SEM; in water mode) and confocal
fluorescence microscopies. The fibrous structure of the hydrogel
can be easily observed in the confocal fluorescent image (Fig. 3a).
The fibers have a width of ca. 2 ꢀm and are hundreds of
micrometer long. These fibrils exhibit green emission which
10 matches with the fluorescent color of the gel. Similar morphology
and dimensions were observed in the SEM measurements (Fig.
3b). In the xerogel, ribbons with widths ranging from 3 to 10 ꢀm
were observed (Fig. S15, ESI†). These thicker structures might
result from the aggregation of the fibrils. These studies
15 corroborate that the selfꢀassembly of 1 into water containing
channels and then fibers is responsible for its gelation properties.
5
Fig. 5 Photographs of a gel pad of compound 1 upon the random addition
of 5 ꢀL solutions of spoiled cod (red circles), fresh cod (blue circles), and
65 water (black circles) under ambient (left) and UV (right) light.
In conclusion, the discovery of a new hydrazoneꢀbased low
molecular weight gelator (1) is described. To the best of our
Fig. 4 pH activated switching of the hydrogel using acid (1M HCl) and
base (1M NaOH) under a) ambient light and b) UV light (365 nm).
knowledge this system (Mw of 241) is one of the smallest
aromaticꢀunit containing hydrogelators reported in the
70 literature. This gel not only exhibits a low critical gelation
concentration (0.1 wt%), but is also strongly emissive in the
gel state. The importance of intraꢀ and intermolecular Hꢀ
bonds in the formation of the gel was established using the
20
Next we investigated the responsiveness of the hydrogel to pH.
The hydrogel collapses upon the addition of 1 equiv of NaOH,32
accompanied by the quenching of fluorescence (Fig. 4). Based on
1H NMR spectroscopic analysis (Fig. S13a, ESI†) the addition of
base leads to the deprotonation of the COOH group, as indicated
25 by the disappearance of the intramolecular Hꢀbond with the
pyridyl nitrogen. Based on the crystal structure, the deprotonation
of COOH will also break the intermolecular Hꢀbonds that form
the dimeric structure of 1 (Fig. 2b). This in turn is expected to
disrupt the selfꢀassembly process and lead to the collapse of the
30 hydrogel. SEM also gives an insight into the effect of pH on the
morphology of the fibers. The addition of 1 equiv of base breaks
down most of the gel’s thick and long ribbon fibers into shorter
rodꢀlike structures having a width of ca. 0.3 ꢀm (Figs. S15b and
S15c, ESI†). This observation indicates that the collapse of the
35 hydrogel upon the addition of base derives from the breaking
down of the fibrous structures. As for the quenching effect, it can
also be attributed to the deprotonation of the COOH group, which
disrupts the ESIPT process. The addition of acid (HCl)
neutralizes the base and the emissive hydrogel reforms.33 This
40 fluorescent “ONꢀOFF” switching process can be cycled for at
least five times.
control compounds
2 and 3, which cannot adequately form
75 such interactions and hence do not act as gelators. The
dependence of gelation and emission on Hꢀbonding allowed
us to use a gel pad in sensing biogenic amines emanating
from spoiled cod. The reversibility of this process and ease
of fabrication open the door to using this soft material in the
80 continuous monitoring of food spoilage,36 among other
applications.
We would like to acknowledge the support of the National
Science Foundation CAREER program (CHEꢀ1253385). We
gratefully acknowledge Dr. Charles P. Daghlian (Dartmouth
85 College) for SEM images, Dr. Ann Lavanway (Dartmouth
College) for confocal fluorescent images (NSF Award
DBI1039423), and Prof. Richard Staples (Michigan State
University) for Xꢀray data.
Notes and references
We took advantage of the pH sensitivity of the emissive gel in
the development of a simple, realꢀtime, and reusable sensor of
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