Halogen-bonding-triggered supramolecular gel formation

Article abstract of DOI:10.1038/nchem.1496

Supramolecular gels are topical soft materials involving the reversible formation of fibrous aggregates using non-covalent interactions. There is significant interest in controlling the properties of such materials by the formation of multicomponent systems, which exhibit non-additive properties emerging from interaction of the components. The use of hydrogen bonding to assemble supramolecular gels in organic solvents is well established. In contrast, the use of halogen bonding to trigger supramolecular gel formation in a two-component gel ('co-gel') is essentially unexplored, and forms the basis for this study. Here, we show that halogen bonding between a pyridyl substituent in a bis(pyridyl urea) and 1,4-diiodotetrafluorobenzene brings about gelation, even in polar media such as aqueous methanol and aqueous dimethylsulfoxide. This demonstrates that halogen bonding is sufficiently strong to interfere with competing gel-inhibitory interactions and create a 'tipping point' in gel assembly. Using this concept, we have prepared a halogen bond donor bis(urea) gelator that forms co-gels with halogen bond acceptors.

Full text of DOI:10.1038/nchem.1496

ARTICLES
PUBLISHED ONLINE: 11 NOVEMBER 2012 | DOI: 10.1038/NCHEM.1496
Halogen-bonding-triggered supramolecular
gel formation
Lorenzo Meazza1,2, Jonathan A. Foster3, Katharina Fucke3, Pierangelo Metrangolo1,2
Giuseppe Resnati1,2 and Jonathan W. Steed3
,
*
*
*
Supramolecular gels are topical soft materials involving the reversible formation of fibrous aggregates using non-covalent
interactions. There is significant interest in controlling the properties of such materials by the formation of
multicomponent systems, which exhibit non-additive properties emerging from interaction of the components. The use of
hydrogen bonding to assemble supramolecular gels in organic solvents is well established. In contrast, the use of halogen
bonding to trigger supramolecular gel formation in a two-component gel (‘co-gel’) is essentially unexplored, and forms the
basis for this study. Here, we show that halogen bonding between a pyridyl substituent in a bis(pyridyl urea) and 1,4-
diiodotetrafluorobenzene brings about gelation, even in polar media such as aqueous methanol and aqueous
dimethylsulfoxide. This demonstrates that halogen bonding is sufficiently strong to interfere with competing gel-inhibitory
interactions and create a ‘tipping point’ in gel assembly. Using this concept, we have prepared a halogen bond donor
bis(urea) gelator that forms co-gels with halogen bond acceptors.
unable gel-phase materials with novel properties such as urea tape hydrogen-bonding motif32–34. These competitive inter-
switchable rheology and controlled flow characteristics are action modes are summarized in Fig. 1.
T
of potential interest in applications as diverse as pharma-
ceutical crystallization, catalysis, drug delivery and controlled as to turn on gelation is a general one, and suggests the possibility of
release, wound healing and the stabilization of drilling mud1–9
manipulating key materials properties and hierarchical self-assem-
Within this context, supramolecular low-molecular-weight gelators bly based on a combination of urea tape formation and a dominant,
(LMWG), with their reversible and dynamic intermolecular inter- crosslinking interaction. Hence, in principle, a detailed understand-
actions, are achieving increasing prominence10–15. Work on switch- ing of supramolecular synthon structure and relative stability
able gels is focused on systems with photo-, pH- and redox-based gleaned from the wealth of crystal engineering literature35–37
Logically, the concept of suppressing an inhibitory interaction so
.
switching, ultrasound-induced gelation and switchable catalysis16–23
.
should provide a means to produce finely balanced, smart materials
To develop smart materials systematically, with controllable and with controllable properties. To demonstrate this approach, we
also well-understood bulk properties, it is necessary to have an turned from metal coordination to the area of halogen bonding38.
understanding of the intermolecular interactions in the system
Halogen bonding—for example, between electron-deficient
and the way in which these interactions engage in hierarchical heavier halogen substituents and halogen bond acceptor atoms
self-assembly to produce emergent morphologies with complex such as basic nitrogen ligands39—is now well established as an
behaviour. However, the link between even primary supramolecular important solid-state interaction in molecular crystals40–42
.
interactions and bulk material properties is often unclear. Recent Recently, halogen bonding has also been demonstrated to be
work has highlighted some simple approaches to controllable or useful in solution, for example in anion binding by pre-organized
smart materials that have met with considerable success.
tripodal anion hosts43. In our hypothesis, halogen bonding should
A key theme is that of setting up a ‘tipping point’ in a system be of sufficient strength to ‘tip the balance’ and engender a switch
comprising competing intermolecular interactions that contribute from pyridyl urea hydrogen bonding to urea tape interactions,
to either gel assembly or gel dissolution. In this regard, a number even in competitive media44,45, and result in multicomponent
of research groups have shown that anion binding in competition gels46–48. We now report the use of halogen bonding to turn on
with urea self-assembly can be used to ‘turn-down’ and ultimately gelation in bis(pyridyl urea) gelators 1 and 2 in the presence of
‘turn-off’ gelation behaviour24,25. Interestingly, in other systems, 1,4-diiodotetrafluorobenzene 3, as well as halogen bonding-
anion binding has also been used to induce gelation26,27. Metal induced gelation in the halogen bond donor gelator 4 when
coordination has been used similarly to tune gel properties25. In a treated with either 4,4′-bipyridine 5, tetrabutylammonium iodide
series of bis(urea) gels we have shown how a combination of or pyridyl derivative 1 (Fig. 2).
metal and anion binding can allow comprehensive control over
the system. Competitive anion binding reduces gel strength by Results and discussion
inhibiting urea a-tape hydrogen bond formation28–31. Conversely, Gelation by competitive inhibition. The previously reported X-ray
metal coordination in pyridyl–urea compounds results in metal crystal structure of 1 shows a combination of urea tape and pyridyl
binding to the pyridyl group, which suppresses the alternative, urea hydrogen-bonding interactions as part of a gradual transition
gel-inhibiting urea–pyridyl hydrogen-bonding interaction, freeing in the dominant intermolecular interaction in the solid state as
the urea groups to form fibrils, and hence gels, as a result of the the length of the oligomethylene chain increases across a series of
1NFMLab-DCMIC ‘Giulio Natta’, Politecnico di Milano, Via L. Mancinelli 7 IT-20131, Italy, 2CNST-IIT@POLIMI, Via G. Pascoli 70/3, IT-20133, Milano, Italy,
3Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK. e-mail: pierangelo.metrangolo@polimi.it; giuseppe.resnati@polimi.it;
*
jon.steed@durham.ac.uk
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.
1

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1496
ARTICLES
a Anion binding turn off
b Metal binding turn off
O
R
R
N
H
N
H
O
O
X–
O
O
N
R
R
R
R
R
N
N
R
R
N
H
N
H
N
H
N
H
N
H
N
H
M+
H
N
H
N
O
O
R
R
N
N
X–
M+
R
R
O
O
N
N
H
N
H
O
H
N
H
N
H
N
H
N
N
H
N
H
M+
HN
HN
O
R
R
R
N
H
N
H
Figure 1 | Manipulation of gel formation and destruction through competitive intermolecular interactions. a, The urea a-tape hydrogen–bonding motif is
responsible for gel fibril formation in bis(urea) LMWG. Competitive anion binding results in a reduction of gel strength because of the strongly competitive
urea–anion interaction. b, Pyridyl ureas are generally poor gelators because of the formation of the pyridyl urea supramolecular synthon, which is not
compatible with fibril formation. Metal coordination frees the urea moieties to produce parallel gel-forming a-tape motifs, crosslinked by metal pyridyl
groups. Halogen bond donors may be substituted for the metal ion.
compounds49. In contrast, the sterically hindered 2 exhibits either 0.4 and 0.5 equivalents of 3 relative to 1 results in a weak, partial gel.
a highly asymmetrical, helical urea hydrogen-bonded motif or Although a 4:1 methanol/water mixture results in optimum
interactions with included solvent50. Compounds 1 and 2 are gelation, gels are formed with other ratios (above 50% methanol)
non-gelators as free ligands, but form a variety of metallogels in as well as with other solvent mixtures, such as acetonitrile/water
the presence of copper(II) and silver(I) salts32–34
.
(.50% MeCN). If the mixture is allowed to cool to room tempera-
Fast cooling from ꢀ60 8C in a dry ice bath of an equimolar sol- ture much more slowly (over a period of 1–2 h), a fibrous crystalline
ution of 1 and 3 in either methanol or mixtures of methanol, aceto- precipitate comprising a 1:1 co-crystal of 1 and 3 is isolated instead
nitrile or dimethylsulfoxide (DMSO) with water (for example, of a gel. Scanning electron microscopy (SEM) analysis of the crystals
.
methanol-water (4:1 vol/vol) mixture at 1% by weight) results in of pure pro-gelator 1 and the corresponding 1 3 co-crystal shows
the formation of an opaque hydrogel. The opacity suggests a rela- that the crystal habit changes from two-dimensional hexagonal
.
tively large fibre size and hence a high degree of crystallinity. The plates to one-dimensional needles on going from 1 to the 1 3
gel-like nature of the material was confirmed by stress sweep rheo- co-crystal (Fig. 3a). This dependence on cooling rate highlights
metry with a plateau elastic modulus (G′) of ꢀ3 kPa and yield stress the close relationship between ordered crystalline material and
of 5 Pa. The G′ value is approximately one order of magnitude above more disordered gels51,52. The structure of the co-crystal material
the G′′ (viscous modulus) value, confirming the solid-like nature of was analysed by single-crystal X-ray crystallography (Fig. 3). The
the material. The gel strength increases in proportion to the amount X-ray structure reveals a conventional nearly symmetrical, double,
of 3 added; in the absence of 3, no gel is formed, but the addition of anti-parallel urea a-tape hydrogen-bonding motif. The pyridyl
groups are involved in a symmetrical halogen-bonding interaction
. . .
with the diiodotetrafluorobenzene, with an N
I distance of
O
2.819(3) Å, consistent with related systems38. The halogen bonds
link one urea tape to another to provide a two-dimensional sheet
structure. For details of the preparations and analysis of gels, see
Supplementary Section S1.
H
N
H
N
N
N
N
H
N
H
O
I
1
F
F
F
F
The dried xerogel was analysed by X-ray powder diffraction
(XRPD), which showed a close match between the xerogel and the
XRPD pattern calculated from the single-crystal structure. This
suggests that the gel has the same structure as the crystals, with gela-
tion a result of the more disordered network morphology forming
on fast cooling (see Supplementary Information).
H
H
H
H
I
N
N
N
N
N
N
3
O
O
2
Generality of the halogen bond-induced gelation mechanism.
Compound 2, because of its highly sterically hindered nature, has
N
N
F
F
a
strong tendency to form solvates and is not strongly
I
F
O
F
F
5
predisposed to form a symmetrical urea tape hydrogen-bonding
motif. However, rapid cooling of a 5:4 (vol/vol) methanol–water
mixture containing equimolar amounts of 2 and 3 also resulted in
the formation of a fairly robust gel, albeit only at concentrations
above 1% by weight of the gelator components. The gel was
characterized by stress sweep rheometry, where a G′ of ꢀ1 kPa,
one order of magnitude larger than G′′, confirmed the solid-like
H
N
H
N
F
I
F
N
H
N
H
O
F
4
Figure 2 | Chemical formulae of the compounds used to obtain
supramolecular LMWGs. The bis(pyridyl urea) gelators 1 and 2 form co-gels nature of the material. The yield stress proved fairly high at 30 Pa.
in the presence of 1,4-diiodotetrafluorobenzene 3, and the halogen bond
donor bis(urea) derivative 4 forms co-gels when treated with either
4,4′-bipyridine 5, tetrabutylammonium iodide or pyridyl derivative 1.
This gel proved intolerant of variations in the solvent mixture; no
other solvent combinations formed gels, consistent with the
tendency towards solvate formation, presumably as a result of
2
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1496
ARTICLES
a
b
c
Slow
Fast
cooling
cooling
40 µm
40 µm
d
Figure 3 | Gel formation by halogen bonding. a, Rapid cooling of an equimolar mixture of bis(pyridyl urea) 1 and diiodotetrafluorobenzene in
methanol/water (4:1 vol/vol) results in a robust hydrogel, while slow cooling gives a fibrous crystalline precipitate. b, SEM image of crystalline 1, which has a
.
.
plate-like morphology. c, SEM image of 1 3, which has a needle morphology. d, X-ray crystal structure of 1 3 showing the anticipated gel-forming urea–tape
interaction and the halogen-bonding crosslinks involving the pyridyl groups. The crystalline materials in b–d were obtained under slow cooling conditions.
steric difficulties in forming a urea tape hydrogen-bonded motif types of diiodotetrafluorobenzene environment. One molecule of
.
in this system. As with 1 3, slow cooling resulted in the formation 3 engages in halogen-bonding bridges between the pyridyl groups
.
of a fibrous, crystalline precipitate, which was characterized of pairs of molecules of 2 in the same way as for 1 3. However, the
by single-crystal X-ray crystallography (Fig. 4). This material second crystallographically independent diiodotetrafluorobenzene
also proved to be a 1:1 co-crystal of the bis(pyridyl urea) and is not involved in any halogen bonds, but is held in place between
diiodotetrafluorobenzene, which also includes water (formula pairs of m-phenylene groups of the bis(pyridyl urea) backbone by
. .
...
...
2 3 2H2O). The structure, however, exhibits two very different weak H F contacts and residual I I interactions. As a result, one
of the two crystallographically independent pyridyl nitrogen
atoms is not involved in a halogen bond and instead hydrogen-
bonds to solvent water. Both independent urea groups form a six-
membered hydrogen-bonded ring involving an included water
molecule, so there is no urea tape motif present in the system,
perhaps explaining the relatively weak nature of the gel formed by
.
2 3 and its intolerance to solvent variation. Repeated attempts to
isolate non-hydrated structures were unsuccessful.
Comparison of the XRPD patterns of the dried gel and the
pattern simulated from the single-crystal data revealed close simi-
larity, suggesting that the gel adopts the same structure. Water
inclusion as an integral structural element within gel fibres has
precedent and may well further contribute to the very specific
conditions needed to form this gel53.
.
The crystal structure of 1 and those of co-crystals 1 3 and
. .
2 3 2H2O were analysed by the Partial Atomic Charges and
Hardness (PACHA)54,55 method based on the observed X-ray coor-
dinates. The structure of pure 1 contains three different types of
hydrogen bond involving the urea groups. The first corresponds
to the urea a-tapes found in the gels and has an energy (by
PACHA) of 28.8 kJ mol21 per bond (four per molecule)—a weak
to medium-strength hydrogen bond. Each molecule also forms
two instances of a second type of hydrogen bond from a urea
N–H to the urea carbonyl group on an adjacent molecule. These
have energies of 211.1 kJ mol21—stronger because the interaction
Figure 4 | Halogen bonding and water inclusion in the hydrate gel
. .
...
2 3 2H2O. The N I halogen-bonding motif links pairs of dipyridyl molecules
through one pyridyl group, while the other pyridyl unit interacts with
included water. A second independent molecule of diiodotetrafluorobenzene
does not engage in any halogen bonding and stacks between pairs of
m-phenylene groups of the bis(pyridyl urea) backbone. There is no direct
urea a-tape interaction.
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
3
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1496
ARTICLES
a
b
c
d
e
f
1µm
Figure 5 | Halogen bonding gel formation by two-component mixtures based on compound 4. a–e, Mixtures are 1% by weight of 4 in DMSO/water (3:1)
either alone (a), or in the presence of potential co-gel-forming halogen bond donors pyridine (b), 4,4′-bipyridine (c), tetra-n-butylammonium iodide (d) and
tetramethyl ethylenediamine (e). Gels are formed only in c and d. However, the iodide gel in d breaks down over a period of ꢀ3 h under ambient conditions.
f, SEM image of the dried gel obtained with bipyridine (c).
is more direct and more linear. The third hydrogen bond is donated the perfluoroaryl groups. In fact, 4 proved to be soluble only in
from the remaining free urea N–H group to the pyridyl group of an DMSO and DMSO–water mixtures, and was a non-gelator in
adjacent molecule (two interactions per molecule) and is stabilized these media.
with an energy of 25.1 kJ mol21. In total, this structure is stabilized
However, if halogen bonding to the urea carbonyl is inhibiting
by hydrogen bonds amounting to 267.6 kJ mol21, among other gel formation, then gelation should be turned on by the addition
.
interactions. In co-crystal 1 3, the hydrogen-bonding scheme of stronger halogen-bonding acceptors. Accordingly samples of
changes. The pyridyl group is involved in the halogen bond, gelator 4 at 1% by weight in DMSO/water (3:1) were treated with
which, with an energy of 26.7 kJ mol21, is slightly more favourable 1–4 molar equivalents of a range of possible halogen-bonding part-
than the urea–pyridyl hydrogen bond in pure 1. In addition, this ners, namely pyridine, 4,4′-bipyridine, iodide (as the tetra-n-buty-
halogen bond facilitates the formation of a total of eight hydrogen lammonium salt) and tetramethyl ethylenediamine (TMEDA).
bonds in the urea a-tape with a total energy of 276.3 kJ mol21
.
The mixtures were heated with sonication to give complete dissol-
Thus, the hydrogen bonding and halogen bonding account for a ution, then allowed to cool to room temperature over a period of
total energy of 289.4 kJ mol21
.
1–2 h. No gels were observed in the pyridine- or TMEDA-contain-
In the structure of 2 3 2H2O, the halogen bonding contributes ing samples. However, both the 4,4′-bipyridine and tetrabutyl-
an energy of 25.2 kJ mol21 per bond to the overall lattice energy. ammonium iodide two-component mixtures gelled effectively
Interestingly, a very low energy of 22.9 kJ mol21 is exhibited by (Fig. 5). Gels were characterized by a simple inversion test, SEM
. .
...
the I I interactions between the two molecules of 3. However, the and by stress sweep rheometry. The iodide-containing gel proved
whole structure is dominated by several strong hydrogen bonds to be relatively weak and unstable, gradually losing cohesion over
between the urea and pyridyl groups of 2 and the water molecules a period of ꢀ3 h for all compositions. The bipyridine co-gel
(Fig. 4), which stabilizes the overall lattice by 22–30 kJ mol21 per proved to be stable indefinitely, however. Interestingly, unlike the
.
bond. The halogen bonding in this case facilitates the host–water two-component gels based on 3, the 4 bipyridine system formed
interaction in combination with the sterically hindered geometry without the need for rapid cooling and was far less crystalline in
of the dipyridyl component. Crucially, the halogen bond energies appearance, with much smaller fibres, as shown by the SEM micro-
of 26.7 kJ mol21 and 25.2 kJ mol21 in the two co-crystals compare graph of the xerogel in Fig. 5f. The much less crystalline nature
favourably with the strength of the urea–pyridyl hydrogen bond of the gel was also demonstrated by the XRPD pattern of the
in the structure of free 1 (25.1 kJ mol21) obtained by the same xerogel, which displayed very broad peaks consistent with limited
.
method, suggesting that the halogen bond is indeed competitive long-range order. The 4 bipyridine co-gel proved to be relatively
with the urea–pyridyl interaction. weak when examined by stress sweep rheometry, but its strength
Attempts were also made to form gels or co-crystals between 1 improved with increasing amount of bipyridine. Indeed, the 1:1
and weaker halogen bond donors, namely 1,4-dibromotetrafluoro- mixture was only just self-supporting, but both the G′ value and
benzene and 1,4-diiodobenzene56. However, no gelation or co-crystal yield stress increased when bipyridine was added, such that a 1:3
.
formation was observed in any case, confirming the requirement mixture was of comparable elastic modulus to the 2 3 co-gel
...
for halogen bonding strong enough to compete with urea pyridyl (1 kPa) and of slightly higher yield stress (60 Pa). However, the
hydrogen bonding in polar media.
generally poorly reproducible nature of the rheometry data suggests
that this difference is not likely to be significant.
A halogen bond donor bis(urea). If halogen bonding-induced
The fact that the gel does not form successfully with TMEDA is
gelation is a general phenomenon then it should be possible to attributed to the insolubility of the two-component system, which
design a halogen-bonding donor gelator combining bis(urea) precipitates in solid form under our experimental gelation con-
and perfluoroaryliodide components in the same molecule. ditions. On the other hand, lack of gelation with pyridine suggests
Accordingly, compound 4 was designed and synthesized from that a bifunctional donor is required to crosslink adjacent urea
4-iodotetrafluoroaniline and the 1,4-diisocyanatobutane. It is a-tape strands into sheets, with their resultant enhanced
unclear from a theoretical standpoint whether 4 would be mechanical robustness.
expected to be a single-component gelator in its own right.
The successful gelation with bipyridine suggests that gelation
Although the presence of the bis(urea) functionality could in might also be expected for combinations of halogen bond donor
principle bring about gel fibre formation, halogen bonding from bis(urea) 4 and halogen bond acceptor bis(pyridyl urea) 1.
the urea carbonyl lone pairs to the electron-deficient iodo groups Accordingly, gelation was attempted for a mixture of 1 and 4 total-
could interfere with urea a-tape formation, so gelation will ling 1% by weight (that is, 0.5% of each component) in
depend on factors such as the relative strength of these competing DMSO/water 3:1 vol/vol. The mixture was warmed to provide
interactions as well as factors such as the p-stacking propensity of complete dissolution, and a transparent brown gel formed upon
4
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1496
ARTICLES
AR2000. Samples prepared for SEM were applied directly to silicon wafer chips
(Agar Scientific) using a cocktail stick for gels or pipettes for liquids, and the solvent
was allowed to evaporate. Samples were stored under vacuum at 1 × 1025 mbar then
sputter-coated with 5 nm platinum in a Cressington 328 coating unit, at 40 mA
(density 21.09 and tooling set at 1), with rotation and a 3008 angle of tilt.
Samples were imaged using a Hitachi S-5200 field-emission scanning electron
microscope at 1.5 kV. Crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre: CCDC 905040 (1 3); CCDC 905041 (2 3).
Compound 4, a solution of 2,3,5,6-tetrafluoro-4-iodoaniline57 (0.7 g, 2.4 mmol)
and triethylamine (0.045 ml) in 2 ml of toluene, was added dropwise, over several
hours, to a refluxing solution of 1,4-butane diisocyanate (0.152 ml, 1.2 mmol) in
5 ml toluene. The mixture was then stirred under reflux for 4 days and the resulting
precipitate isolated by filtration before being purified by trituration in methanol.
Yield 0.34 g, 0.48 mmol, 40%; m.p. 217–219 8C; 19F NMR (DMSO-d6), d ¼ 2124.25
(d, 2F), 2145.33 (d, 2F); 1H NMR (DMSO-d6), d ¼ 1.43 (m, 2CH2), 3.08 (m, 2CH2),
6.55 (s, 2NH), 8.35 (s, 2NH); HR-MS ES2: m/z 720.8865 [M–H]2, calc. for
C18H11N4O2F8I2, 720.8844.
a
b
.
.
Received 16 April 2012; accepted 9 October 2012;
published online 11 November 2012
c
References
1. Smith, D. K. in Organic Nanostructures (eds Atwood, J. L. & Steedin, J. W.)
111–154 (Wiley-VCH, 2008).
2. Hirst, A. R., Escuder, B., Miravet, J. F. & Smith, D. K. High-tech applications
of self-assembling supramolecular nanostructured gel-phase materials: from
regenerative medicine to electronic devices. Angew. Chem. Int. Ed. 47,
8002–8018 (2008).
3. Foster, J. A. et al. Supramolecular gels: anion-switchable media for controlling
crystal growth. Nature Chem. 2, 1037–1043 (2010).
4. Li, H., Fujiki, Y., Sada, K. & Estroff, L. A. Gel incorporation inside of organic
single crystals grown in agarose hydrogels. CrystEngComm 13, 1060–1062 (2011).
5. Estroff, L. A. & Hamilton, A. D. Water gelation by small organic molecules.
Chem. Rev. 104, 1201–1217 (2004).
6. Estroff, L. A., Addadi, L., Weiner, S. & Hamilton, A. D. An organic hydrogel as a
matrix for the growth of calcite crystals. Org. Biomol. Chem. 2, 137–141 (2004).
7. Van Bommel, K. J. C., Stuart, M. C. A., Feringa, B. L. & van Esch, J. Two-stage
enzyme mediated drug release from LMWG hydrogels. Org. Biomol. Chem. 3,
2917–2920 (2005).
8. Yang, Z. et al. Self-assembly of small molecules affords multifunctional
supramolecular hydrogels for topically treating simulated uranium wounds.
Chem. Commun. 4414–4416 (2005).
5µm
Figure 6 | Co-gel formation between halogen bond acceptor and halogen
bond donor bis(urea)s 1 and 4. a,b, Compound 4 in DMSO/water (3:1)
.
does not undergo gelation (a), but in the presence of 1 it forms co-gel 1 4
´
in DMSO/water (3:1) (b). c, SEM image showing the morphology of the
9. Escuder, B., Rodrıguez-Llansola, F. & Miravet, J. F. Supramolecular gels as active
media for organic reactions and catalysis. New J. Chem. 34, 1044–1054 (2010).
10. Terech, P. & Weiss, R. G. Low molecular mass gelators of organic liquids and the
properties of their gels. Chem. Rev. 97, 3133–3160 (1997).
11. Dastidar, P. Supramolecular gelling agents: can they be designed?
Chem. Soc. Rev. 37, 2699–2715 (2008).
.
1 4 co-gel.
cooling. The gel proved relatively weak, but comparable in strength
to the bipyridine analogue. Examination of the xerogel by SEM
revealed an intricate network of thin, homogeneous fibres 12. Fages, F. Metal coordination to assist molecular gelation. Angew. Chem. Int. Ed.
45, 1680–1682 (2006).
13. Foster, J. A. & Steed, J. W. Exploiting cavities in supramolecular gels.
Angew. Chem. Int. Ed. 49, 6718–6724 (2010).
14. Maeda, H. Anion-responsive supramolecular gels. Chem. Eur. J. 14,
showing some co-alignment on the scale of tens of micrometres,
linked by a more disordered secondary mesh of material (Fig. 6).
The very thin fibres are consistent with the optical transparency
of the gel, in contrast to the opaque co-gels formed with 3.
11274–11282 (2008).
15. Steed, J. W. Supramolecular gel chemistry: developments over the last decade.
Chem. Commun. 47, 1379–1383 (2011).
Conclusions
´
16. Rodrıguez-Llansola, F., Escuder, B. & Miravet, J. F. Switchable perfomance
In summary, we have shown that halogen bonding—even in polar,
aqueous media—is sufficiently strong to tip the balance between two
competing supramolecular synthons and favour fibre formation and
hence gelation, in a manner similar to metal coordination by
bis(pyridyl urea) gelators. Halogen bonding is a versatile, general
gel-forming interaction that may be incorporated into either the
gelator structure or introduced through a gel-forming partner
compound. The addition of halogen bonding to the toolbox of
controllable supramolecular gel formation substantially expands
the possibilities for manipulating these smart soft materials and
eliminates complications arising from metal coordination to
solvent, anions and other components of the gel.
of an l-proline-derived basic catalyst controlled by supramolecular gelation.
J. Am. Chem. Soc. 131, 11478–11484 (2009).
17. Yang, H. et al. Switchable fluorescent organogels and mesomorphic
superstructure based on naphthalene derivatives. Langmuir 23,
8224–8230 (2007).
18. Hsueh, S-Y. et al. Acid/base- and anion-controllable organogels formed from a
urea-based molecular switch. Angew. Chem. Int. Ed. 49, 9170–9173 (2010).
19. Zhang, S. Y. et al. Ultrasound-induced switching of sheetlike coordination
polymer microparticles to nanofibers capable of gelating solvents.
J. Am. Chem. Soc. 131, 1689–1691 (2009).
20. Dutta, S., Shome, A., Debnath, S. & Das, P. K. Counterion dependent
hydrogelation of amino acid based amphiphiles: switching from non-gelators
to gelators and facile synthesis of silver nanoparticles. Soft Matter 5,
1607–1620 (2009).
21. Peng, F., Li, G., Liu, X., Wu, S. & Tong, Z. Redox-responsive gel–sol/sol–gel
transition in poly(acrylic acid) aqueous solution containing Fe(III) ions switched
by light. J. Am. Chem. Soc. 130, 16166–16167 (2008).
22. Cravotto, G. & Cintas, P. Molecular self-assembly and patterning induced by
sound waves. The case of gelation. Chem. Soc. Rev. 38, 2684–2697 (2009).
23. Naota, T. & Koori, H. Molecules that assemble by sound: an application
to the instant gelation of stable organic fluids. J. Am. Chem. Soc. 127,
9324–9325 (2005).
Methods
Gel formation was carried out by weighing the appropriate amount of gel
components (ꢀ1 wt%) in a vial and adding a suitable solvent. The suspension
was then sonicated and heated until all solid had dissolved. The sample was then
flash-cooled in a dry ice/acetone bath (278 8C) or allowed to cool under ambient
conditions (21 8C). Rheology was carried out in a parallel-plate geometry using a
40 mm steel plate with a gap of 500 mm on a 4 ml scale using a TA Instruments
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
5
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1496
ARTICLES
24. Steed, J. W. Anion-tuned supramolecular gels: a natural evolution from urea
supramolecular chemistry. Chem. Soc. Rev. 39, 3686–3699 (2010).
25. Piepenbrock, M. O. M., Lloyd, G. O., Clarke, N. & Steed, J. L. Metal- and
anion-binding supramolecular gels. Chem. Rev. 110, 1960–2004 (2010).
26. Becker, T. et al. Proline-functionalised calix[4]arene: an anion-triggered
hydrogelator. Chem. Commun. 3900–3902 (2008).
46. Ryan, D. M., Doran, T. M. & Nilsson, B. L. Complementary p–p interactions
induce multicomponent coassembly into functional fibrils. Langmuir 27,
11145–11156 (2011).
47. Adarsh, N. N., Kumar, D. K. & Dastidar, P. Composites of N,N′-bis-(pyridyl)
urea-dicarboxylic acid as new hydrogelators—a crystal engineering approach.
Tetrahedron 63, 7386–7396 (2007).
27. Shen, J-S., Cai, Q-G., Jiang, Y-B. & Zhang, H-W. Anion-triggered melamine
based self-assembly and hydrogel. Chem. Commun. 46, 6786–6788 (2010).
28. Lloyd, G. O. & Steed, J. W. Anion-tuning of supramolecular gel properties.
Nature Chem. 1, 437–442 (2009).
29. Piepenbrock, M-O. M., Lloyd, G. O., Clarke, N. & Steed, J. W. Gelation is
crucially dependent on functional group orientation and may be tuned by anion
binding. Chem. Commun. 2644–2646 (2008).
30. Lloyd, G. O., Piepenbrock, M-O. M., Foster, J. A., Clarke, N. & Steed, J. W.
Anion tuning of chiral bis(urea) low molecular weight gels. Soft Matter 8,
204–216 (2012).
31. Piepenbrock, M-O. M., Clarke, N., Foster, J. A. & Steed, J. W. Anion tuning and
polymer templating in a simple low molecular weight organogelator.
Chem. Commun. 47, 2095–2097 (2011).
48. Moffat, J. R. & Smith, D. K. Controlled self-sorting in the assembly of
multi-gelator gels. Chem. Commun. 316–318 (2009).
49. Byrne, P., Turner, D. R., Lloyd, G. O., Clarke, N. & Steed, J. W. Gradual
...
...
transition from NH pyridyl hydrogen bonding to the NH O tape synthon in
pyridyl ureas. Cryst. Growth Des. 8, 3335–3344 (2008).
50. Todd, A. M., Anderson, K. M., Byrne, P., Goeta, A. E. & Steed, J. W. Helical or
polar guest-dependent z′¼1.5 or z′¼2 forms of a sterically hindered bis(urea)
clathrate. Cryst. Growth Des. 6, 1750–1752 (2006).
51. Ostuni, E., Kamaras, P. & Weiss, R. G. Novel X-ray method for in situ
determination of gelator strand structure: polymorphism of cholesteryl
anthraquinone-2-carboxylate. Angew. Chem. Int. Ed. Engl. 35,
1324–1326 (1996).
52. George, M., Tan, G., John, V. T. & Weiss, R. G. Urea and thiourea derivatives as
low molecular-mass organogelators. Chem. Eur. J. 11, 3243–3254 (2005).
53. Anderson, K. M. et al. Structure calculation of an elastic hydrogel from
sonication of rigid small molecule components. Angew. Chem. Int. Ed. 47,
1058–1062 (2008).
54. Henry, M. Thermodynamics of hydrogen bond patterns in supramolecular
assemblies of water molecules. ChemPhysChem 3, 607–616 (2002).
55. Henry, M. Nonempirical quantification of molecular interactions in
supramolecular assemblies. ChemPhysChem 3, 561–569 (2002).
56. Walsh, R. B. et al. Crystal engineering through halogen bonding: complexes
of nitrogen heterocycles with organic iodides. Cryst. Growth Des. 1,
165–175 (2001).
32. Byrne, P. et al. Metal-induced gelation in dipyridyl ureas. New J. Chem. 34,
2261–2274 (2010).
33. Piepenbrock, M-O. M., Clarke, N. & Steed, J. W. Shear-induced gelation in a
copper(II) metallogel: new aspects of ion-tunable rheology and gel-reformation
by external chemical stimuli. Soft Matter 6, 3541–3547 (2010).
34. Piepenbrock, M-O. M., Clarke, N. & Steed, J. W. Metal ion and anion based
‘tuning’ of a supramolecular metallogel. Langmuir 25, 8451–8456 (2009).
35. Biradha, K., Su, C-Y. & Vittal, J. J. Recent developments in crystal engineering.
Cryst. Growth Des. 11, 875–886 (2011).
36. Saha, B. K., Nangia, A. & Jaskolski, M. Crystal engineering with hydrogen bonds
and halogen bonds. CrystEngComm 7, 355–358 (2005).
37. Braga, D., Brammer, L. & Champness, N. R. New trends in crystal engineering.
CrystEngComm 7, 1–19 (2005).
57. Wenk, H. H. & Sander, W. 2,3,5,6-Tetrafluorophenylnitren-4-yl: a quartet-
ground-state nitrene radical. Angew. Chem. Int. Ed. 41, 2742–2745 (2002).
38. Metrangolo, P., Meyer, F., Pilati, T., Resnati, G. & Terraneo, G. Halogen bonding
in supramolecular chemistry. Angew. Chem. Int. Ed. 47, 6114–6127 (2008).
39. Metrangolo, P., Meyer, F., Pilati, T., Proserpio, D. M. & Resnati, G. Highly
Acknowledgements
J.W.S., K.F. and J.A.F. acknowledge funding from the Engineering and Physical Sciences
Research Council and GlaxoSmithKline. P.M. and G.R. thank Fondazione Cariplo (project
nos 2009-2550 and 2010-1351) for financial support.
...
interpenetrated supramolecular networks supported by N I halogen bonding.
Chem. Eur. J. 13, 5765–5772 (2007).
40. Metrangolo, P., Neukirch, H., Pilati, T. & Resnati, G. Halogen bonding based
recognition processes: a world parallel to hydrogen bonding. Acc. Chem. Res. 38,
386–395 (2005).
41. Metrangolo, P. & Resnati, G. in Encyclopedia of Supramolecular Chemistry Vol. 1
(eds Atwood, J. L. & Steed, J. W.) 628–635 (Marcel Dekker, 2004).
42. Yan, D. et al. A cocrystal strategy to tune the luminescent properties of
stilbene-type organic solid-state materials. Angew. Chem. Int. Ed. 50,
12483–12486 (2011).
43. Cavallo, G. et al. Halogen bonding: a general route in anion recognition and
coordination. Chem. Soc. Rev. 39, 3772–3783 (2010).
44. Aakero¨y, C. B., Chopade, P. D. & Desper, J. Avoiding ‘synthon crossover’ in
crystal engineering with halogen bonds and hydrogen bonds. Cryst. Growth Des.
11, 5333–5336 (2011).
Author contributions
L.M. and J.A.F. undertook the synthesis of gelators, experimental studies and rheology
measurements. K.F. carried out crystallographic measurements and PACHA calculations.
P.M., G.R. and J.W.S. were responsible for the overall project concept, direction and
coordination. All authors contributed to writing the manuscript.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permission information is available online at
http://www.nature.com/reprints. Correspondence and requests for materials should be
addressed to P.M., G.R. and J.W.S.
45. Aakero¨y, C. B., Chopade, P. D., Ganser, C. & Desper, J. Facile synthesis
and supramolecular chemistry of hydrogen bond/halogen bond-driven
multi-tasking tectons. Chem. Commun. 47, 4688–4690 (2011).
Competing financial interests
The authors declare no competing financial interests.
6
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.