Gelation Landscape Engineering Using a Multi-Reaction Supramolecular Hydrogelator System

Article abstract of DOI:10.1021/jacs.5b06988

Simultaneous control of the kinetics and thermodynamics of two different types of covalent chemistry allows pathway selectivity in the formation of hydrogelating molecules from a complex reaction network. This can lead to a range of hydrogel materials with vastly different properties, starting from a set of simple starting compounds and reaction conditions. Chemical reaction between a trialdehyde and the tuberculosis drug isoniazid can form one, two, or three hydrazone connectivity products, meaning kinetic gelation pathways can be addressed. Simultaneously, thermodynamics control the formation of either a keto or an enol tautomer of the products, again resulting in vastly different materials. Overall, this shows that careful navigation of a reaction landscape using both kinetic and thermodynamic selectivity can be used to control material selection from a complex reaction network.

Full text of DOI:10.1021/jacs.5b06988

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Communication
Gelation Landscape Engineering using a Multi-
Reaction Supramolecular Hydrogelator System
Jamie S. Foster, Justyna M. Zurek, Nuno M. S. Almeida, Wouter E. Hendriksen, Vincent
A. A. le Sage, Vasudevan Lakshminarayanan, Amber L. Thompson, Rahul Banerjee,
Rienk Eelkema, Helen Mulvana, Martin J. Paterson, Jan H. van Esch, and Gareth O. Lloyd
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b06988 • Publication Date (Web): 26 Oct 2015
Downloaded from http://pubs.acs.org on November 2, 2015
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Gelation Landscape Engineering using a Multi-Reaction Su-
pramolecular Hydrogelator System
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†
†
†
§
Jamie S. Foster, Justyna M. Żurek, Nuno M. S. Almeida, Wouter E. Hendriksen, Vincent A. A. le
∥
⊥
§
§
§
Sage, Vasudevan Lakshminarayanan, Amber L. Thompson, Rahul Banerjee, Rienk Eelkema, Helen
Mulvana, Martin J. Paterson, Jan H. van Esch and Gareth O. Lloyd*
‡
†
†
§
† Institute of Chemical Sciences, School of Engineering and Physical Sciences, Heriot-Watt University, William Perkin
Building, Edinburgh, Scotland, United Kingdom, EH14 4AS
§ Advanced Soft Matter Group, Department of Chemical Engineering, Delft University of Technology, Julianalaan 136,
2628BL, Delft, the Netherlands
⊥ Chemical Crystallography, Oxford University, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, United King-
dom, OX1 3TA
∥ Polymers and Advanced Materials Laboratory, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, In-
dia
‡ School of Engineering, James Watt South Building, University of Glasgow, Glasgow, Scotland, United Kingdom, G12
8QQ
Supporting Information
drug delivery and templates for crystal, particle or cell growth, to
name but a few.3 With this in mind, research groups from around
the world have studied these materials for a number of years
through the use of pre-synthesised low molecular compounds
which undergo supramolecular polymerisation. More recently,
research has begun to exploit chemical reactivity to both form and
deform the gelatinous materials and to sample the pathway com-
plexity of the self-assembly, but to date have not utilised the
chemical reaction pathways to control selectivity.4 These reported
works have generally focused on single step reactivity and have
not researched multi-step reactivity or two or more types of reac-
tivity in a single gelation system. Further work has begun to ap-
pear in which catalytic control over chemical reactivity is utilised
to control the assembly processes of the gel components and
therefore the material properties and spatial distribution of the
material.5 This has led to many elegant methodologies to tackle
the pathway complexity of supramolecular assembly in which
kinetic and thermodynamic materials are isolated. With this in
mind we hypothesised that chemical reactivity could play an im-
portant role in the production of multiple materials by controlling
pathway selection in complex reaction networks (instead of the
supramolecular assembly landscape).4 To do this we introduced
multiple step reactivity (kinetic control) and pH dependent tau-
tomerisation (thermodynamic control) to a reaction network capa-
ble of reversibly and irreversibly forming of a range of potential
hydrogelators from set of simple starting chemicals (Fig. 1). In the
present case, this results in three distinct gel materials from effec-
tively the same chemical starting point (a mixed solution of the
reactants).
ABSTRACT: Simultaneous control of the kinetics and thermo-
dynamics of two different types of covalent chemistry results in
pathway selectivity in the formation of hydrogelating molecules
from a complex reaction network. This can lead to a range of
hydrogel materials with vastly different properties, starting from a
set of simple starting compounds and reaction conditions. Chemi-
cal reactivity between a trialdehyde and the tuberculosis drug
isoniazid can result in the formation of either one, two or three
hydrazone connectivity products meaning kinetic gelation path-
ways can be addressed. Simultaneously, the thermodynamics
control the formation of either a keto or an enol tautomer of the
products, again resulting in vastly different materials. Overall, this
shows that careful navigation of a reaction landscape using both
kinetic and thermodynamic selectivity can be used to control ma-
terial selection from a complex reaction network.
Both thermodynamic and kinetic parameters controlling self-
assembly processes can be used to control pathway selection in
the assembly of supramolecular materials. The resultant assem-
blies or materials can have vastly different properties, depending
on the chosen self-assembly path.1 Thermodynamically, pushing
an assembly down a certain pathway to a stable energy well with-
in the assembly landscape can utilise solvent, temperature or pH
changes. Kinetically, the landscape can be navigated using the
activation energies associated with certain assembly processes, to
address metastable states over time or to kinetically trap a certain
state. Materials generated from these complex pathways include
crystal forms (polymorphism), viruses, protein networks, supra-
molecular polymers and certain low molecular weight gelators
(LMWGs).1 LMWGs represent the main materials of interest in
this article but the principles of the research may be applied to any
supramolecular assembly process. LMWGs are an important class
of supramolecular materials used to immobilise a large variety of
solvents.2 LMWGs have been utilised and envisioned having a
number of applications; these include commercial products in
In situ covalent bond formation between the water soluble trial-
dehyde 1,3,5-triformylphoroglucinol (Ie) and the tuberculosis drug
isoniazid (Isonicotinic acid hydrazide, II) resulted in the for-
mation of discotic compounds capable of acting as hydrogelators.
This reactivity between hydrazides and aldehydes is well-known
for its use in dynamic covalent chemistry.6
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Figure 1. The pathway complexity reaction network diagram (left) shows the supramolecular assembly of three hydrogels from a single
starting point (*) of dissolved core and periphery components. The multiple step reactivity (horizontal arrows) between a core trialdehyde
(Ie orange triangle) with a periphery hydrazide (II black semi-curve) samples kinetically the assembly landscape. Thermodynamic con-
trolled tautomerisation (hooked vertical arrows between orange (enol) to purple (keto) triangles) samples a different part of the conjectural
gelation landscape. Self-assembly (vertical thick black arrows) from the chemical reactivity products is resultant of the process conditions
which selects the reaction product giving three distinct gelatinous materials. Be (orange pathway), Ce (red pathway), and Ck (yellow path-
way). Ae is the mono-substituted enol intermediate observed experimentally. Ie crystallises out at low pH (< 7) values in water.
Hydrazone formation can be catalysed by protons or hydroxyl
anions as well as by certain amines, and although this catalysis
can occur in our system it has no effect on the kinetic or thermo-
dynamic selectivity of the complex reaction pathway.7 The reac-
tion pathway of Ie and II should give three possible enol hydra-
zone species, products Ae, Be and Ce and three possible keto hy-
drazone species Ak, Bk and Ck (Fig. 1); referring to a singly, dou-
bly and triply reacted set of products, respectively. The triply
reacted product is found in two tautomeric forms, enol (Ce) and
keto (Ck), while Ae and Be are observed experimentally.
more robust having both a higher G' value and “yield stress” than
the Ck gel (Fig. 2 and Figs. S2 – S4, S5 – S7). The critical gela-
tion concentration (CGC) for Ce and Ck are 0.2 % and 0.5 % by
weight, respectively, also indicating a difference in the materials.
Further rheological studies provided evidence on the connectivity
between the supramolecular fibres of Ce and Ck. The effect on the
rheology with increase in concentration of Ce revealed a good
match with the cellular solid/SAFIN models for gels.4, 5 The tem-
poral changes during the kinetics of the gelation process also pro-
vide insights into the assembly process. The determination of the
Avrami constants (also known as fractal dimensions) for Ce and
Ck, 2.4 and 1.4 respectively, reveal a strong contrast in the assem-
bly processes and connectivity explaining the rheological differ-
ences. The self-assembled materials were found to be not only
physically different but also chemically. Isolation of Ce or Ck
from these gels generated two distinct, analytically different tau-
tomers (see S.I. for details of isolation through simple filtration
and washes). NMR, UV/Vis absorption (compared to the calculat-
ed spectra), IR and mass spectrum analyses indicate that the tau-
tomers isolated from the two pH ranges do result in Ce at low pH
and Ck at high pH. This pH dependent thermodynamic control
selects the gelation pathway for Ce and Ck. The calculated reac-
tion pathways and energy differences between the two tautomers,
Ce and Ck, were determined to be relatively small: in the C3 ge-
ometry. Ck, as expected, is more stable.9 Ce is kinetically trapped
in a metastable state (See S.I. computational calculations indicate
Ck is 0.6 kcal/mol more stable than Ce and the reaction pathway
has high energy transition states (7 – 10 kcal/mol)).
There are a number of ways in which to set gels formed from
this reactive molecular system. Reaction conditions can result in
three different gels, namely the Ce, Ck and Be gels (Figure 1).
Gels are heat and time stable. The methodologies in brief for syn-
thesising the gels are (see S.I. for details):
1. Mix the core Ie with a number of equivalents of II at pH 8
and raise the pH to 9.5 – 12. This results in Ck gel, compound Ck
is chemically the thermodynamically stable monomer. Equiva-
lents of reactants, salts or mode of changing the pH do not change
the experimental outcome;
2. Mix the core Ie with a number of equivalents of II at pH 8
and leave in solution for a set period of time (hours) before lower-
ing the pH utilizing glucono-δ-lactone (GdL).8 This results in the
Ce gel. Compound Ce is a kinetically trapped monomer, in refer-
ence to tautomerisation, with Ck being more stable;
3. Mix the core Ie with a number of equivalents of II at pH 8
and immediately on mixing lower the pH utilizing GdL at room
temperature. The lowered pH results in the Be gel if the correct
time variable within the reaction kinetics from reacting I and II
through Ae to Be, and not Ce, is obtained. This is the kinetic selec-
tivity of an intermediate monomer in the stepped reaction se-
quence.
The setting of these gels is also reversible indicating the tau-
tomerisation is fully reversible (gelation reversibility is via the
dissolved pH 8 species). To the best of our knowledge this is the
first example of reversibility of the keto-enol tautomerisation in
this class of compounds in water.9 At pH 8 the fully soluble Ce
species appears to be an anion in the form of either the mono-
deprotonated or doubly deprotonated species as evidenced by
mass spectrometry and UV/Vis spectroscopy (see S.I.). This indi-
cates that the low pH gelation trigger for Ce is the protonation of
the anion resulting in a very low solubility neutral compound. The
apparent pKa determination for Ce resulted in a value of approxi-
mately 6.8 (+/- 0.1). The results also indicate that as the pH is
Gelation methodologies 1 and 2 result in the formation of two
different gels, the Ck gel (high pH) and the Ce gel (low pH), both
of which are triple-hydrazone compounds. The gels are distinctly
different in terms of not only their rheological characteristics but
also their colour (Figs. 1 and 2). The Ce gel is red in colouration
whereas the Ck gel is yellow; the colour is indicative of the tau-
tomeric form and is therefore chemically based. The Ce gel is
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increased the position of the tautomer equilibrium between Ce and
exclusively made from Be. Rheological concentration studies and
Ck is shifted (OH– induced, Fig. S50). The pH change results in a
compound which should have a very high pKa, Ck, which is neu-
tral and once again has a low solubility and self-assembles into
the gelatinous material.9, 10 Chemical synthesis of Ce and gel set-
ting of the dissolved Ce species at pH 8 results in the same gel
formation as the in situ gelation method (i.e. an ex situ gelation
method, see S.I. for details). This indicates the gelation pathway is
only dependent on the tautomerisation covalent chemistry and not
the hydrazone reactivity.
the Avrami constant (2.2) for Be gels show the gels also follow
the cellular solid theory of gels and are highly inter-connected
gelatinous materials. All three gels are fibrous in nature as seen in
the SEM morphologies. PXRD stacking distances are in the range
3.32 – 3.39 Å for all three types of gels, very similar to that
known for benzene-1,3,5-triamide supramolecular polymers and
gels, indicating recognisable molecular packing motifs, as con-
firmed by computational work and crystal structures.9c, 9d, 9f, 11 We
investigated trimers of structures Be, Ce, and Ck using B97D with
a 6-311g(d) basis. We have previously used this level of theory to
satisfactorily explain aggregated supramolecular structures in
similar systems. Ce, Ck and Be revealed their propensity to form
supramolecular polymers but also the key difference in Be form-
ing structurally different aggregates. These are all indicative of
fibre formation through supramolecular polymerisation resulting
in gelation.2
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The relation between the formation of the Be gel material and
the kinetics of the reactions in different solution conditions was
followed utilising mass spectrometry and UV-Vis spectroscopy,
to better understand the relationship between the chemical reactiv-
ity and the self-assembly of the gels (see SI for varied experi-
mental settings). Figure 3 shows the reaction of Ie and II at pH 8
and indicates the immediate (seconds timescale) formation of Ae
upon mixing Ie and II. Within seconds/minutes of mixing, Be is
formed resulting in the almost complete depletion of Ie and Ae.
However, the formation of Ce is not observed in most cases until
at least five to ten minutes into the reaction. The rate of formation
of Ce is dependent of the amount and type of catalyst present, i.e.
pH. For example, Ce is formed completely within minutes at pH
10 (OH– catalyst) as noted by the quick gelation of Ck utilising
gel method 2, compared to hours for formation at pH 8. Ce always
forms at high pH (pH > 7) as Be is fully soluble at these pHs and
does not undergo tautomerisation. At lower pHs (< 7) a competi-
tion between formation of Ce from Be and the self-assembly of Be
is established.
Figure 2. Rheological frequency range sweeps of the gels show-
ing the three different gel types Ce, Ck and Be having three dis-
tinct rheological properties with approximate G' values of 11000
Pa, 800 Pa and 3000 Pa, respectively. Ce gels are shown as: Filled
black  ex situ gel; Empty  gel method 2. Ck gels are shown as:
Grey  ex situ gel; Empty  gelation and mixing at pH 10;
Filled black  gel method 1. Be gels are shown as: Filled black ▲
gel method 3; Empty  ex situ gel.
The importance of the pyridyl groups in the cross-linking of the
supramolecular polymers is highlighted by the fact that the phenyl
versions of Ce and Ck, De and Dk, form supramolecular polymers
but do not crosslink to form a gel network (see S.I. for synthesis
and chemical structure details). Crystallisation of Ce and Ck and
determination of the crystal structures reveal that the both mole-
cules are indeed the enol tautomer (the first such crystallographic
determinations of enol forms of this class of molecules)9 and both
show the propensity to stack one of top of each other due to their
discotic shape (see S.I. for details of structures). The De tape motif
is built from a discrete 푅2888 hydrogen bonding pattern (based on
Graph Set hydrogen bonding patterns from Margaret Etter) which
involves the methanol solvent interrupting the well-known 1,3,5-
benzene triamide hydrogen bonding patterns.9c, 9d, 9f, 11, 12 The Ce
structure does not show this hydrogen bonding as it crystallises
with DMSO which acts as a strong hydrogen bonding acceptor,
again following the Margaret Etter rules.12 This however does not
prevent the molecule from forming a stacking assemble showing
that the dispersion forces and shape are sufficient to induce su-
pramolecular polymerisation. The pyridyl groups are not interact-
ing directly with each other to cross-link the columns of Ce, how-
ever, well known hydrogen bonding patterns with water may play
an important role in cross-linking the hydrogel networks.13
Figure 3. Reaction pathway kinetics in solution for the formation
of anion versions of Ae, Be and Ce. Conversion of Ie (shown as
empty ) and II (at a ratio of 1 to 6, respectively) to Ce (shown as
dark grey filled ) via intermediates Ae (shown as solid black )
and Be (shown as grey filled ) at a constant pH 8 in water. Po-
tential “gelling zones” based on the occurrence for Be and Ce are
shown as light grey (first ten minutes) and dark grey zones (after
several hours), respectively. Solid lines are used as a guide for the
eye. II is not shown for clarity. a) Full time of analysis of the
reaction b) inset showing first ten minutes of the same analysis.
Varying the ratios of Ie and II in the initial solution using
methods 1 and 2 always resulted in Ck and Ce gels, respectively.
Therefore Ck and Ce gel production is essentially independent of
stoichiometry (see S.I. for details). When gelation method 3 was
utilised a different gel was formed, made up of the twice reacted
gelator Be rather than the thrice reacted Ce materials, illustrating
the kinetic selectivity within the reaction gelation landscape. The
majority of cases utilising gelation method 3 resulted in the gels
being orange in colour and gave rheologically weaker materials
compared to the Ce gels but stronger than the Ck gels (Fig. 2 and
Figs. S18 – S20). Isolation of the chemical component of these
orange gels (see S.I. for details) revealed that the materials were
The reaction kinetics give clear evidence on why the methodol-
ogy for gelation (method 3 compared to 2) results in two distinct
materials. GdL addition to the gelation mixture method 3 results
in a drop in pH to below 6.6 (apparent pKa for Be is 6.6 (+/- 0.1))
indicating that the metastable Be is kinetically trapped through
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Baskakov, I. V; Legname, G.; Baldwin, M. A.; Prusiner, S. B.; Cohen, F.
self-assembly. The explanation for this kinetic trapping is the
mass transfer limitation of Be from the solid state network of the
gel, resulting in limited concentration and low reactivity in solu-
tion (see S.I. for details). Indeed, increasing the pH of a gel made
using method 3 above a pH 6.6 to resolubilise the compounds
results in Be reacting further to generate Ce in solution (without
any further addition of II). Again lowering the pH below the ap-
parent pKa of Ce results in a Ce gel. This gel cannot be converted
back to a Be gel without extensive chemical isolation (i.e. theoret-
ical breaking of covalent bonds between Ie and II and isolation of
individual species). Isolated Be is indeed capable of forming gels
through the pH triggered mechanism as indicated by the rheology,
morphology and appearance of the gels made from dissolving
isolated pure Be at pH 8 and lowering the pH. The CGCs of Be
from both methodologies were identical at 0.3 % by weight. Un-
like Ce, when Be is added to a high pH water solution no gelation
occurs and a clear coloured solution results, indicative of a soluble
deprotonated species.
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Supporting information includes chemical synthesis and analysis,
rheology, electron microscopy, chemical kinetics analysis, crystal-
lography (SuperFlip and CRYSTALS)15 and computational work.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Bhat, V. T.; Caniard, A. M.; Luksch, T.; Brenk, R.; Campopiano, D. J.;
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Hackeng, T. M.; Dawson, P. E. J. Am. Chem. Soc. 2006, 128, 15602.
AUTHOR INFORMATION
Corresponding Author
* g.o.lloyd@hw.ac.uk
(8)
Adams, D. J.; Butler, M. F.; Frith, W. J.; Kirkland, M.; Mullen,
L.; Sanderson, P. Soft Matter 2009, 5, 1856.
(9)
Notes
(a)Yelamaggad, C. V; Achalkumar, A. S.; Shankar Rao, D. S.;
Prasad, S. K. J. Am. Chem. Soc. 2004, 126, 6506. (b) Chong, J. H.; Sauer,
M.; Patrick, B. O.; MacLachlan, M. J. Org. Lett. 2003, 5, 3823. (c)
Kandambeth, S.; Mallick, A.; Lukose, B.; Mane, M. V; Heine, T.;
Banerjee, R. J. Am. Chem. Soc. 2012, 134, 19524. (d) Plaul, D.; Plass, W.
Inorganica Chim. Acta 2011, 374, 341. (e) Riddle, J. A.; Lathrop, S. P.;
Bollinger, J. C.; Lee, D. J. Am. Chem. Soc. 2006, 128, 10986. (f)
Jędrzejewska, H.; Wierzbicki, M.; Cmoch, P.; Rissanen, K.; Szumna, A.
Angew. Chem. Int. Ed. 2014, 53, 13760.
(10)
G. J. Chem. Soc. Perkin Trans. 2 1985, 11, 1711.
(11) Howe, R. C. T.; Smalley, A. P.; Guttenplan, A. P. M.; Doggett,
M. W. R.; Eddleston, M. D.; Tan, J. C.; Lloyd, G. O. Chem. Commun.
2013, 49, 4268.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
GOL, JSF thank Heriot-Watt University, the Royal Society of
Edinburgh/Scottish Government Fellowship (GOL) and the Scot-
tish Funding Council Exchange Scheme (GOL) for funding. GOL
and HM thank the Scottish Crucible for the project award “Cus-
tom Bubbles”.
Carey, A. R. E.; Fukata, G.; O’Ferrall, R. A. M.; Murphy, M.
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