pubs.acs.org/Langmuir © 2009 American Chemical Society
We Can Design Molecular Gelators, But Do We Understand Them?† Jan H. van Esch* Self Assembling Systems, Delft ChemTech, Delft University of Technology, Julianalaan 136, 2628BL Delft, The Netherlands Received May 14, 2009 The recent application of supramolecular principles to the design of molecular gelators has led to an enormous variety of new gelators and functional gels but has contributed relatively little to the understanding of molecular gelation phenomena. How do we progress from here?
Introduction The past 15 years have witnessed a true revival of lowmolecular-weight (LMW) gelators not only because of the many potential applications but also because the formation of LMW gels is an example par excellence of molecular self-assembly. This recent interest in LMW gelators has followed decades of low activity since the 1930s, during which the first molecular gelators and their applications as thickeners in lubricants, printing inks, and napalm were developed. Whereas in earlier years the discovery of new gelators was almost exclusively a matter of serendipity, the recent application of supramolecular principles to the design of new gelators has boosted the field. Nowadays more than 1000 LMW gelators1 have been described, and it has become seemingly straightforward to modify molecular gel materials and introduce tailor-made functionalities by chemical modification at the molecular level.
Molecular Gelators Can Be Designed The first attempts to design molecular gelators originate from the mid-1990 by the group of Hanabusa, Shinkai, and Hamilton and several other groups including ours.2 A clear recipe for a gelator molecule such as that existing for surfactants could not yet be identified because of the enormous structural diversity of known LMW gelators; nevertheless, some common structural features started to appear. Moreover, molecular gel systems have in common that the gelator forms a continuous 3D entangled network in the solvent, thereby preventing the liquid from flowing. In contrast to inorganic and macromolecular gels, the solid network structure of molecular gels results from the selfassembly of LMW gelator molecules solely through noncovalent interactions, and as a result, network formation and hence gelation are fully thermoreversible.3 This crude understanding of molecular gels has led to the formulation of the following rules for the design of LMW gelators:4 (i) the presence of strong selfcomplementary and unidirectional intermolecular interactions to enforce 1D self-assembly, (ii) control of fiber-solvent interfacial energy to control solubility and to prevent crystallization, and † Part of the Molecular and Polymer Gels; Materials with Self-Assembled Fibrillar Networks special issue.
(1) The number of more than 1000 gelators is a rough estimate. (2) van Esch, J. H.; Feringa, B. L. Angew. Chem., Int. Ed. 2000, 39, 2263–2266. (3) Weiss, R. G.; Terech, P., Eds.; Molecular Gels; Springer: Dordrecht, The Netherlands, 2006. (4) Hanabusa, K.; Yamada, M.; Kimura, M.; Shirai, H. Angew. Chem., Int. Ed. 1996, 35, 1949–1951.
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(iii) some factor to induce fiber cross-linking for network formation. These very basic guidelines have enabled the development of several new LMW gelators systems for organic solvents, water, and even supercritical carbon dioxide.5,6 However, despite these accomplishments, the design of new gelators based on first principles continues to be largely a trial-and-error process in which successes are often outnumbered by failures. In recent years, several new approaches have emerged from the literature in order to cope with the empirical nature of finding new gelators. In 2000, Miyata and co-workers reported on a combinatorial approach by using a library of bile acids and aliphatic amines.7 In this work, they took advantage of in situ salt formation upon mixing solutions of the acid and base, which in many cases gave a precipitate but in some cases led to the formation of a gel. An analysis of the gels confirmed that they indeed consists of the anticipated salts of bile acid and amine, and further analysis by electron microscopy and X-ray diffraction provided some insight into the packing mode. The elimination of the need for synthesizing and purifying gelator candidates, the fast identification of new gelator candidates, and its applicability to larger libraries of other potential gelator precursors has inspired several other groups to adopt this approach to explore a variety of two-component gelling systems. In such systems, two components can combine either through the formation of a covalent bond8 or solely through noncovalent interactions to form the active gelator, allowing for in situ gel formation and fine tuning of the gel properties by modifying only one component.9,10 The library approach is not limited to gelator candidates that can be prepared in situ, but can also be applied to ex situ-prepared compounds in multistep synthesis procedures by the application of solid-phase synthetic methods.11 Another promising and more rational approach along these lines is the screening for gel formation properties from libraries of supramolecular synthons, which were selected from X-ray crystal structures on the basis of the (5) de Loos, M.; Feringa, B. L.; van Esch, J. H. Eur. J. Org. Chem. 2005, 17, 3615–3631. (6) Hirst, A. R.; Escuder, B.; Miravet, J. F.; Smith, D. K. Angew. Chem., Int. Ed. 2008, 47, 8002–8018. (7) Nakano, K.; Hishikawa, Y.; Sada, K.; Miyata, M.; Hanabusa, K. Chem. Lett. 2000, 1170–1171. (8) Suzuki, M.; Nakajima, Y.; Yumoto, M.; Kimura, M.; Shirai, H.; Hanabusa, K. Langmuir 2003, 19, 8622–8624. (9) Hirst, A.; Miravet, J.; Escuder, B.; Noirez, L.; Castelletto, V.; Hamley, I.; Smith, D. Chem.;Eur. J. 2009, 15, 372–379. (10) Suzuki, M.; Saito, H.; Hanabusa, K. Langmuir 2009, 25, 10.1021/la8040924. (11) Kiyonaka, S.; Shinkai, S.; Hamachi, H. Chem.;Eur. J. 2003, 9, 976– 983.
Published on Web 06/18/2009
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preservation of particular 1D and 2D self-assembly motives.12 Although this approach has the distinct advantage of enabling correlations between the packing mode in the crystal structure and the presence (absence) of gelation properties, one has to keep in mind that the packing mode in the gel and crystalline states are not necessarily the same. Most implementations of the library approach to gel research still require the preparation and testing of individual samples of each library member, and in this regard, they are clearly different from the traditional library approach in drug delivery that aims for the selection of active compounds from pools of thousands of compounds. Lehn and co-workers and more recently Li and coworkers have also been able to identify new LMW gelators from mixtures of precursor compounds.13,14 To this extent, they studied gel formation by molecules that were formed in situ from an amine and an aldehyde through the reversible formation of an imine bond. Here, gel formation acts as a selection mechanism by displacing the dynamic imine formation equilibrium toward the most potent gelating combination of aldehyde and amine, which, most interestingly, also renders the systems adaptive to changes in external and internal conditions. It should be noted that most of these studies are based on already-known gelator structures as a starting point and the resulting new gelators are only marginally different from the parent compounds. A similar strategy is also followed in the gelator scaffold approach or, to speak with Dastidar, the molecular engineering approach.12 In this approach, a known LMW gelator is covalently modified with appropriate moieties to tune solvent compatibility or introduce the required functionality. For instance, hydrogen bonding scaffolds, which are scaffolds based on 1,3,5-trisamide-cyclohexane, β-sheet-forming peptides, glutamic acid tris amides, and also organic salts and rigid moieties such as steroids have all been successful applied to provide a variety of functional molecules with gelating properties.12 The best results have been obtained when well-soluble functional molecules are modified with poorly soluble gelator scaffolds for a particular solvent system. Also, the opposite approach of starting from an insoluble functional group and improving its solubility by the attachment of solvophilic groups has also led to some successes, as long as the insoluble group provided anisotropic intermolecular interactions, eventually by the attachment of additional anisotropic interactions from amides. At this point, the guidelines start to become similar to the first principles design rules, making it difficult to draw a sharp line between them.
Do We Understand Molecular Gels? All of the approaches discussed so far are pragmatic in the sense that they reduce serendipity. They might even be called successful as long as they are judged only by the criterion “gelation-no gelation”. A closer look at currently known LMW gelators and their gels reveals enormous structural diversity, which is accompanied by an equally large variation in solvent scope, thermotropic and mechanical properties, and gel morphology. In some cases, it has been possible to make qualitative correlations between, on the one hand, molecular structure and intermolecular interactions and, on the other hand, solvent scope and thermotropic properties, but so far there are hardly any clues for correlating fiber and gel morphology and mechanical properties with molecular structure. The actual situation is even worse (12) Dastidar, P. Chem. Soc. Rev. 2008, 37, 2699–2715. (13) Sreenivasachary, N.; Lehn, J. M. Proc. Nat. Acad. Sci. U.S.A. 2005, 102, 5938–5943. (14) Wang, G.-T.; Lin, J.-B.; Jiang, X.-K.; Li, Z.-T. Langmuir 2009, 25, 10.1021/ la804188z.
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because of the numerous examples of compounds that are structurally very similar to a gelator but yet do not gelate, often for unknown reasons. Apparently, there are still several mysteries behind molecular gelation phenomena, despite the recent progress in the design of molecular gelators. This lack of insight into molecular gelation phenomena can be traced back to two different origins. First, there is a large gap between our design efforts and actual knowledge of the supramolecular structure of the gels (i.e., the molecular arrangement of gelator molecules within the gel fibers, the junction zones, and the fiber-liquid interface). As a consequence, the feedback loop between molecular design and experimental verification remains at the qualitative gelation-no gelation level, without leading to significant improvement of design and insights. This situation will change only when more detailed information on the molecular arrangement within the gel fibers becomes available. Limited knowledge on the supramolecular structure is not exclusive for molecular gels but reflects a general issue in supramolecular science because current experimental techniques remain inadequate to provide structural details at the supramolecular level for anything other than crystals and proteins. Currently, for several examples of LMW gelators the supramolecular packing has been resolved by extrapolation from X-ray studies on single crystals, providing some very useful insights.15,16 However, for most examples, it remains unclear whether this packing is preserved in the gel fibers; moreover, comparisons with nongelling analogues are mostly absent. In this issue, the group of Desvergne and Del Guerzo report on X-ray studies of gelating and nongelating members of the well-studied gelator class of 2,3dialkoxyanthracenes.17 They found that the nongelling members adopt a herringbone arrangement that is usual for aromatic groups. Most interestingly, the gelators form triads that are packed head-to-tail in layered structures. Although it is not yet unambiguously clear whether this unusual arrangement is preserved in the gel fibers, this example shows once more that it is not justified to depict a molecular structure for gel fibers by simple extrapolation from common supramolecular motives or crystal structures. Here, new approaches to elucidate the supramolecular structure of nanosized assemblies are badly needed. Powder18,19 and fiber diffraction20,21 methods seems to be very promising for molecular gel systems and can be used with solvated fibers; however, complications might arise from the less ordered and often polycrystalline nature of gel fibers. Recently, promising examples of such approaches have been reported by the groups of Oda and Shimizu, who have been able to get detailed insight into the actual supramolecular arrangement within the gel fibers by combining powder diffraction methods or high-resolution transmission electron microscopy (TEM) with molecular modeling.22,23 More research along these lines for other gel systems is definitely needed and will open the possibility to tackle urgent and challenging issues such as the development of molecular models (15) Menger, F.; Caran, K. J. Am. Chem. Soc. 2000, 122, 11679–11691. (16) van Esch, J.; Schoonbeek, F.; de Loos, M.; Kooijman, H.; Spek, A.; Kellogg, R.; Feringa, B. Chem.;Eur. J. 1999, 5, 937–950. (17) Olive, A. G. L.; Raffy, G.; Allouchi, H.; Leger, J.-M.; Del Guerzo, A.; Desvergne, J.-P. Langmuir 2009, 25, 10.1021/la804206n. (18) Abdallah, D.; Sirchio, S.; Weiss, R. Langmuir 2000, 16, 7558–7561. (19) Oda, R.; Artzner, F.; Laguerre, M.; Huc, I. J. Am. Chem. Soc. 2008, 130, 14705–14712. (20) Orgel, J. P.; Irving, T. C.; Miller, A.; Wess, T. J. Proc. Natl. Acad. Sci. U.S. A. 2006, 103, 9001–9005. (21) Percec, V.; Rudick, J. G.; Peterca, M.; Yurchenko, M. E.; Smidrkal, J.; Heiney, P. A. Chem.;Eur. J. 2008, 14, 3355–3362. (22) Yui, H.; Minamikawa, H.; Danev, R.; Nagayama, K.; Kamiya, S.; Shimizu, T. Langmuir 2008, 24, 709–713. (23) Oda, R.; Artzner, F.; Laguerre, M.; Huc, I. J. Am. Chem. Soc. 2008, 130, 14705–14712.
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for fiber structure and network formation and the implementation of existing theories on crystal habit or mechanical properties of networks within the near future. The second origin of the current lack of insight into molecular gelation phenomena lies in our limited knowledge of the energetic landscape of gel formation. This is particularly relevant because most gel systems are in a metastable state and hence their formation is governed by thermodynamics and kinetics. The metastable nature of the gel state is also apparent from the limited long-term stability of many molecular gels, which often gradually transform into crystals. The relative stabilities of the gel and crystal state are very likely to depend strongly on the solvent properties, which also holds for other important gel characteristics such as fiber diameter, intertwining and fission, network mesh size, and junction zone density. Despite its importance, the role of the solvent is still poorly understood, leading to phrases such as “a delicate balance between solubility and gelation and solvent properties”. One reason for this poor understanding is that only very recently the groups of Smith and Miravet proposed a thermodynamic model corroborated by quantitative studies that takes network morphology into account.24 A second reason for this poor understanding might be the ambipolar nature of LMW gelators, which consist in most cases of one or more solvophilic parts and a solvophobic part. In a quantitative study in this issue, we have been able to show that the relative contributions of hydrogen bonding and aliphatic groups to the stability of gels completely revert in going from apolar to polar solvents.25 As a consequence, correlations between gel and solvent properties are nonlinear and therefore are often obscured in qualitative studies. Future work along these physical organic chemistry lines might benefit from the great progress in drug design by application of structure-activity relationships studies in combination with molecular modeling approaches. Whereas such studies will provide new insights into structure-activity relationships for molecular gelators, relatively few efforts have been made to explore the role of kinetics in gel formation, especially in relation to fiber and network morphology. So far, kinetic studies have been mainly carried out by rheology and various spectroscopic techniques, often in combination with Xray and neutron scattering.26 Here, the application of cryo-TEM tomography will be very powerful in providing time-resolved information in direct space.27 Such studies are essential to extending current kinetic models for gel formation28 and will (24) Hirst, A. R.; Coates, I. A.; Boucheteau, T. R.; Miravet, J. F.; Escuder, B.; Castelletto, V.; Smith, D. K. J. Am. Chem. Soc. 2008, 130, 9113–9121. (25) Zweep, N.; Hopkinson, A.; Meetsma, A.; Browne, W. R.; Feringa, B. L.; van Esch, J. H. Langmuir 2009, 25, 10.1021/la9004714. (26) Terech, P.; Pasquier, D.; Bordas, V.; Rossat, C. Langmuir 2000, 16, 4485– 4494. (27) Parry, A. L.; Bomans, P. H. H.; Holder, S. J.; Sommerdijk, N. A. J. M.; Biagini, S. C. G. Angew. Chem., Int. Ed. 2008, 47, 8859–8862.
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allow for the rational fine tuning of fiber and gel morphology by additives.29 Only by such a combination of thermodynamic and kinetic studies on gel formation will it be possible to explore the solvent-gelator landscape in a rational way and develop quantitative rules for the de novo design of molecular gelators. However, it should be realized that such detailed studies are resourceintensive and therefore should be focused on a couple of wellchosen representative model systems for molecular gelators.
Where Are We Going, and Where Should We Go? At a first glance, the successful molecular design of new, functional LMW gelators is a victory of the molecular programming approach, the central paradigm in supramolecular chemistry, according to which a molecular scaffold can be programmed with an interaction algoritm to form a predefined supramolecular structure. In view of its success, the molecular design approach toward LMW gelators has been shown to be an excellent, pragmatic starting point for research projects motivated by the numerous potential applications of molecular gels. Although these novel concepts and applications of molecular gels attract much interest both from fellow scientists and funding agencies, at some point these academic, proof-of-concept studies should lead to the development of real-world applications. Such application development is very likely to be accompanied by the ability to optimize properties such as the shelf life, appearance, texture, and porosity, which are all related to the morphology, thermal stability, and viscoelastic properties. From this perspective, it will be wise to redirect at least part of the ever-limited research capacity from short-term proof-of-concept studies toward more resource-demanding fundamental studies. The molecular design of LMW gels also seems to be a valid approach for curiosity-driven research on molecular gelation phenomena, gaining additional motivation from a proposition by Richard Feynman, who wrote on his blackboard “What I cannot create I do not understand.”30 But at this point, one has to be careful. Although the Feynman proposition is valid for many cases, it does not imply that the opposite; “what I can create I do understand” is also true. Therefore, following up on the success of the molecular design of LMW gelators, we have to ask ourselves every now and then whether our apparent ability to create or design new molecular gels has led to a real understanding of molecular gelation phenomena. Acknowledgment. This work was supported by The Netherlands Organization for Scientific Research (NWO). (28) Liu, X.; Sawant, P. Adv. Mater. 2002, 14, 421–426. (29) Liu, X.; Sawant, P.; Tan, W.; Noor, I.; Pramesti, C.; Chen, B. J. Am. Chem. Soc. 2002, 124, 15055–15063. (30) Richard Feynman on his blackboard at time of his death in 1988, as quoted in “The Universe in a Nutshell” by Stephen Hawking.
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