A family of simple benzene 1,3,5-tricarboxamide (BTA) aromatic carboxylic acid hydrogels

Article abstract of DOI:10.1039/c2cc37428e

We present the characterisation of a hydrogel forming family of benzene 1,3,5-tricarboxamide (BTA) aromatic carboxylic acid derivatives. The simple, easy to synthesise compounds presented here exhibit consistent gel formation at low concentrations through the use of a pH trigger.

Full text of DOI:10.1039/c2cc37428e

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A family of simple benzene 1,3,5-tricarboxamide (BTA)
aromatic carboxylic acid hydrogels†
Cite this: DOI: 10.1039/c2cc37428e
Richard C. T. Howe,a Adam P. Smalley,a Alexander P. M. Guttenplan,a
Matthew W. R. Doggett,a Mark D. Eddleston,a Jin Chong Tanb and
Gareth O. Lloyd*a
Received 11th October 2012,
Accepted 7th December 2012
DOI: 10.1039/c2cc37428e
www.rsc.org/chemcomm
We present the characterisation of a hydrogel forming family of
benzene 1,3,5-tricarboxamide (BTA) aromatic carboxylic acid
derivatives. The simple, easy to synthesise compounds presented here
exhibit consistent gel formation at low concentrations through the use
of a pH trigger.
There are an ever increasing number of families of hydrogel
forming low molecular weight gelators (LMWGs). Examples
include the peptides functionalised with napthyl, FMOC or BOC
groups; many varieties of small molecule peptides; the cholesterol
family; the sugar-based gelators; and cyclohexyl bisamide-,
Scheme 1 The eight compounds utilised in this study.
trisamide- and bisurea-compounds.1 All of these hydrogelators based on N-protected peptides has shown how the carboxylic acid
have proven to be incredibly interesting and applicable, especially protonation and salt formation can act as a predictable trigger
as alternatives to conventional biological and synthetic polymers. between solvated species, the salt form, and a self-assembled
Applications in drug delivery, cell growth media, crystal growth insoluble material, the protonated form. This led us to utilise
media, energy capture, and microelectronics are universally BTA compounds with peripheral aromatic carboxylic acids. This
recognised as being future technology uses for these materials.1,2 design strategy for the hydrogel family was confirmed recently as
Even with the large variety in chemical functionality available for having good potential in a recent publication by Schmidt and
material design and applications, there is still a need to increase Albuquerque.6 We have thus synthesised a series of compounds,
the chemical and physical variety within the building blocks for tested their gelation ability and characterised the hydrogels.
these soft materials. When trying to design a new family of
The eight compounds, 1–8, utilised in this study (Scheme 1)
hydrogels, the use of a chemically robust principal self-assembly were synthesised through the reaction between 1,3,5-benzene-
moiety is required that can be easily and systematically modified tricarbonyl trichloride and the corresponding amino aromatic
to vary the properties of the materials.3 When selecting this moiety carboxylic acid in THF and an excess of triethylamine (see ESI†
we turned to a well-studied supramolecular assembly chemistry in for details). All compounds were synthesised in good yields and
the form of the C3 symmetric benzene 1,3,5-tricarboxamide (BTA) as crystalline white solids. They were found to be insoluble in
motif.4 Not only does it provide a robust supramolecular motif, it deionised water. However, upon the addition of three equivalents
can be easily varied chemically in the form of the outer functiona- of NaOH the materials dissolved, except for compound 7, which is
lity (Scheme 1). This moiety is also structurally similar to the insoluble even at pH 12. Addition of small amounts of acid in the
archetypical cyclohexyl triamide gelators that were introduced a form of dilute HCl resulted in gelation of compounds 1–5 (Fig. 1).
decade ago by Feringa and van Esch.5 Recent work on hydrogels
Compound 8 formed a precipitate upon the decrease in pH and
was therefore not found to form a gel. This implies that the
hydrogen bonding between the amides is crucial to gel formation.
In the case of compound 6, no precipitate or gel was observed at
any pH. Upon standing for several weeks, crystallisation of trimesic
acid occurred. This suggests that the increased hydrolysis potential
of the amide bond, due to the electron-withdrawing fluorine
a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
CB2 1EW, UK. E-mail: gol20@cam.ac.uk; Fax: +44 (0)1223 336362;
Tel: +44 (0)1223763989
b Department of Engineering Science, University of Oxford, Parks Road, Oxford,
OX1 3PJ, UK
† Electronic supplementary information (ESI) available: Compound synthesis
and analysis, TEM, cryo-SEM, Rheology and PXRD. See DOI: 10.1039/c2cc37428e groups in compound 6, has resulted in an unstable compound.
c
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Table 1 Rheology characteristics of gels at 1% by weight
Compound G0 (Pa) G00 (Pa) Yield stress (mNm) CGCa (by weight%)
1
2
3
4
5
4000 230
1150 50
9200 390
1100
2500
12 700
1000
800
0.2
0.1
0.1
0.1
0.2
13 500 400
470
50
Fig. 1 Photographs of the gels formed by, from left to right, compounds 1 to 5.
a
Critical gel concentration.
imposed with a fixed frequency (1 Hz) over a range of shear stress
amplitudes. The gels showed a typical G0 value, essentially constant
below the critical value of oscillatory torque (‘‘yield stress’’). At this
yield stress point, the sample starts to flow. From these experiments
it is clear that the rheology defined ‘‘strengths’’ of the gels are in the
order 3–4 > 1–2 > 5 (Table 1). Kinetic information can be obtained
from the rheological data. We utilised the storage modulus temporal
changes to follow the kinetics of all five gelators.11 As it is well known
that the formation of the fibrous networks result from nucleation
and growth mechanisms, we applied the Avrami equation to the
kinetics of gel formation.11 These analyses resulted in determination
of Avrami constants, which can be interpreted in terms of both a
Fig. 2 Graph showing calculated pKa and clog P values for the compounds utilised in
this study, firstly comparing clog P values of neutral (greenB) and tri-anionic species
(red n) against calculated pKa values. Secondly, calculated neutral clog P values against
measured apparent pKa values (blue J) for the five gelators.
The gels formed by the addition of HCl were found to be nucleation and growth mechanism, and as a fractal dimension.11
inhomogeneous materials. For this reason, we utilised the gelators In this work we have interpreted the data in terms of the Avrami
as salts, which are easily precipitated from water at high pH, and constant. We determined the Avrami constant, with an error of
that are soluble in neutral water. Homogenous gelation followed approximately 0.1, for each of the gels to be 1.9, 2.0, 1.7, 1.0 and 1.9
when the addition of three equivalents of glucono-d-lactone was for the gels 1 to 5, respectively. We can thus suggest the gelation
used as a substitute for the HCl (see ESI† for details).7 This method mechanism for compound 1, 2, 3 and 5 to be based on homogeneous
has been successfully utilised in a number of studies of dipeptide spontaneous nucleation, interfacial control, and one-dimensional
gelators and indeed for the gelation by 1 as described in the paper by growth. Compound 4, with an Avrami constant of 1.0, thus shows
Schmidt and Albuquerque.6,7 The pH at which the gelation occurs is a gelation mechanism based on heterogeneous nucleation, interfacial
an important variable in these materials, especially in terms of the control, and one-dimensional growth. Further studies are currently
possible biological applications.7 We thus determined the apparent being performed to establish the reasons behind these differences,
pKa of the gelators and compared these to predicted values for the these are most likely connected to the level of supersaturation.11b
hydrophobicity (clog P) and pKa (Fig. 2).8 Two points of interest can A concentration study of the rheology of compound 1 shows the
be found from this data. Firstly, upon deprotonation the hydro- relationship between concentration and strength of the gel, in the
phobicity of the compounds decreases significantly allowing for the form of the yield stress, to be yield stress p concentration1.82. This
solubilising of the compounds and the desolvation upon protona- indicated that the gel conforms to the cellular solid model and not a
tion. It would be of importance to see if this type of analysis could be colloidal gel description.12 The cellular solid model describes an
utilised to predict other types of chemical triggers for gelation, such open-cell cellular material which consists of load bearing struts
as chemical fuels.9 The second point of interest is that the predicted interconnected via crosslinks or junction points which deform by
pKa are, on average, 2.2 values lower than the measured apparent bending. These two rheology-based results, the Avrami constant and
pKa values. This has been noted in the dipeptide compounds the concentration p yield stress relationship indicate growth of
calculations and measurements, and is due to the assembly process one-dimensional supramolecular fibres following nucleation, which
creating hydrophobic character affecting the pKa’s of the compound, results in a cellular solid gel matrix. This was confirmed by the
a process well known in proteins.8
cryo-SEM and TEM analysis of the materials, as shown in Fig. 3
The behaviour of the fibres of the gels when exposed to mechani- (ESI,† Fig. S3–S8). All samples were found to have a fibrous gel
cal stress was investigated using rheometry (Table 1, see ESI† for matrix with fibre width diameters of approximately 50–200 nm.
details, Fig. S9–S23).10 Frequency sweep rheometry with a small
Electron diffraction analysis of the samples showed that the
amplitude stress, revealed the solid-like nature of the gels at 20 1C fibres are amorphous with no distinct diffraction spots. However,
with the storage modulus, G0, being typically an order of magnitude there is a recognisable halo ring in all the samples analysed, which
greater than the loss modulus, G00. The G0 values were consistent gives d spacings (3% error) of 3.39 Å, 3.41 Å, 3.48 Å, 3.41 Å and 3.50 Å
over a wide range of frequencies. This viscoelastic behaviour is for compounds 1 to 5, respectively. The powder diffraction patterns
associated with classical gels and therefore supports the notion that for the dried gels showed a similar characteristic broad reflection at
the change in pH of these samples, which caused a change from a 3.47 Å, 3.38 Å, 3.44 Å, 3.41 Å and 3.50 Å for compounds 1 to 5,
clear solution to a solid-like material, indeed resulted in a true gel respectively (ESI,† Fig. S2). A comparison of the recently reported
state. The non-linear rheological response was investigated using crystal structure of compound 1, several other BTA crystal structures
stress sweep experiments, during which an oscillatory torque was and with the d spacings found from the gel materials gives evidence
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We thank Prof. Anthony Cheetham, Prof. William (Bill)
ˇ
ˇ
Jones, Dr Dejan-Kresimir Bucar for use of equipment. We thank
the following for financial support, the Herchel Smith Fund
and CAS of Chemistry (Cambridge), the Royal Society, the
EPSRC Cambridge NanoDTC EP/G037221/1, the European
¨
Research Council and the EU INTERREG IVA 2 Mers Seas Zeeen
Cross-border Cooperation Programme.
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Chem. Commun.