The Design of Molecular Gelators

NIEK ZWEEP AND JAN H. VAN ESCH

1.1 Introduction

Supramolecular gels are hot! Since 1990 the number of publications on supramolecular gels has increased from less than five to at least five hundred papers per year. The current interest in supramolecular gels has followed a long period of silence after their original discovery in the 1930s, when it was found that certain low molecular weight organic compounds could turn organic solvents into a gelly-like substance. Because of this property they found widespread use as thickeners and lubricants, but at that time they did not raise much scientific interest. It took until the rise of supramolecular chemistry in the 1970s and 1980s, to realise that gel formation by these low molecular weight compounds is an example of a supramolecular system par excellence.

But what are gels? In daily life most people encounter gels, often without realising it. From a scientific point of view, the gel state has been recognised already for over 150 years. Nevertheless, the definition of a gel has long been under debate, mainly the term "gel" may point to chemically and physically very diverse systems. 3In 1861 Thomas Graham gave the following description: "while the rigidity of the crystalline structure shuts out external expressions, the softness of the gelatinous colloid partakes of fluidity, and enables the colloid to become a medium for liquid diffusion, like water itself."

In the years that followed scientists attempted to define the "gel" state in a more explicit manner. Dorothy Jordon Lloyd wrote in 1926 that the colloidal condition, the "gel" state, is easier to recognise than to define and proposed: "only one rule seems to hold for all gels and that is that they must be built up from two components, one which is a liquid at the temperature under consideration and the other which, the gelling substance proper, often spoken of as the gelator, is a solid. The gel itself has the mechanical properties of a solid, i.e. it can maintain its form under stress of its own weight and under any mechanical stress it shows the phenomenon of strain". Ever since, more rigorous definitions were proposed in attempts to link the microscopic and macroscopic properties of a gel. Based on these definitions a substance is a gel if it (1) has a continuous microscopic structure with macroscopic dimensions that is permanent on the time scale of analytical experiments and (2) is solid-like in its rheological behaviour despite being mostly liquid.

In general, a gaseous or liquid system consisting of two or more components turns into a gel when one of the components forms a 3-dimensional (3D) en-tangled solid network within the bulk gas or liquid phase. The presence of this solid network restricts flow of the remaining gas or liquid bulk phase, and as a result the whole system appears macroscopically as a solid. Following this description, there are several possibilities to classify gels, e.g. according to the chemical nature of the components, or the physical state of the bulk phase.

A very common and useful classification is to distinguish between chemical and physical gels (Figure 1.1). Chemical gels are gels in which formation of the 3D network has occurred through covalent crosslinking of the network components, resulting in a permanent network structure unless the covalent crosslinks are broken. Examples of such chemical gels include many crosslinked polymeric systems used in separation technology, and inorganic aerogels used as thermal insulators. In physical gels, formation of the 3D network has occurred through the formation of noncovalent interactions between the network components, and hence, the formation of physical gels is usually thermo-reversible. Physical gels can be formed by many, very different combinations of substances, for instance with clays, polymers, proteins, colloids, and certain small organic compounds as network-forming component in, for instance, organic solvents or water as the liquid component.

Supramolecular gels are thus a type of physical gels that are formed by small organic compounds as network-forming component. These small organic compounds are called low molecular weight gelators (LMWGs). LMWGs are gelators consisting of organic compounds with a molecular weight of less than 2000 Da, that are capable of gelling organic solvents or water. Depending on whether the liquid phase is an organic solvent or water, they are also known as organogelators or hydrogelators, respectively. Gels from LMGWs are most commonly prepared by cooling a solution of the LMWG in the solvent to be gelled, leading to a supersaturated solution. The supersaturation causes a rapid assembly of the gelator molecules into elongated fibres of typically 5–100 nm diameter, and subsequently these fibres aggregate into a fibrous 3D entangled network, thereby turning the liquid into a supramolecular gel. Such a supra-molecular gel consists of an entangled fibrous network of gelator molecules, which is held together by highly specific intermolecular interactions between the gelator molecules.

Hence, supramolecular gels are a clear manifestation of supramolecular chemistry in action. A central paradigm in supramolecular chemistry is that one can design supramolecular devices and materials with a desired function, by programming the assembly properties of their molecular building blocks via molecular shape and intermolecular interactions. Therefore, over and over the question arose whether it would also be possible to design new supramolecular gels with tailor-made properties, by following the guidelines and principles of supramolecular chemistry. This chapter deals with the design of supramolecular gels. First, a brief introduction to the different types of LMW gelators as well as the main characteristics of supramolecular gels will be given, and then we will discuss the current status in the design of supramolecular gels.

1.2 Intermolecular Interactions in Molecular Gels

There are many different LMWGs with very different structures. However, despite the structural diversity, they have in common that their self-assembly into fibrous networks is driven by noncovalent interactions, like van der Waals interactions, π-interactions, dipolar interactions, hydrogen bonding, and coulomb interactions. Also, solvophobic effects play an important role. These solvophobic effects originate from moieties or functional groups in the gelator molecule that are poorly soluble in the solvent to be gelled, and contribute to the gelating ability by reducing the overall solubility of the gelator in that solvent. Some examples of well-known LMWGs are given in Figure 1.2.

A large group of gelators is related to amphiphiles. Amongst the oldest of gelators known are metallic soaps, which are used in cosmetic applications. An example of a metallic soap gelator is the lithium salt of 3-hydroxy stearic acid 1. Gelator 1 is based on 12-hydroxystearic acid, which is obtained from castor oil. This gelator aggregates via several intermolecular interactions: ionic interactions between the metal ions, van der Waals interactions between the alkyl tails and hydrogen-bonding interactions between hydroxyl groups. Cationic surfactants are structurally related to the metallic soaps. Quaternary ammonium salts with long alkyl chains, like compound 2 show gelation behaviour due to aggregation driven by Coulomb interactions, as well as the poor solubility of the quarternary ammonium moiety in many organic solvents.

Less obvious cases of amphiphile-type gelators are 3 and 4. Gelator 3 is a perfluorcarbon-hydrocarbon block-compound, of which in hydrocarbon solvents the perfluoroblock is insoluble and hence solvophobic, whereas the aliphatic part is very soluble, and hence solvophylic. At room temperature compound 3 is immiscible with aliphatic hydrocarbons, leading to phase separation and gel formation at concentrations as low as 2 (w/w)%. Also, bis(alkyloxy)anthracene 4 can be considered as an amphiphile for hydrocarbon solvents, with the aliphatic hydrocarbon and anthracene moieties as solvophylic and solvophobic parts, respectively. Apart from solvophobic effects aggregation of 4 is also controlled by π-interactions and van der Waals interactions.

In addition to solvophobic effects and specific intermolecular interactions, conformational rigidity may also contribute to the gelation ability. For instance, many steroids like cholesterol 5, but also cholic acids are efficient gelators for various organic solvents. The strong aggregation behaviour of these compounds is thought to originate in their molecular rigidity, which reduces entropic losses upon aggregation. Also, dibenzilydene-D-sorbitol (DBS) 6, a simple sugar derivative and known since 1942 as an efficient gelator for both organic solvents and water, is a fairly rigid molecule with little conformational freedom.

In the above examples hydrogen bonds are mostly absent or contribute only little to their aggregation behaviour. For many gelator molecules, however, hydrogen-bonding interactions are essential for their gelation ability. For instance, simple peptides like 7 or even without alkyl chains have been reported to gelate a range of different organic solvents, due to the formation of strong hydrogen bonds between the peptide amide groups. Another well-known example of an amino acid based gelator is dibenzoylcysteine 8, which is a very potent hydrogelator capable of gelling water at concentrations as low as 2 mM or (0.1% by weight). With this compound again solvophobic effects, or more precisely hydrophobic effects because of the special character of water, and ITLπITL-interactions between the pendant benzyl groups make a major contribution to the stability of its aggregates.

1.3 Structure and Properties of Molecular Gels

The gelators systems discussed above have been known for over 20 years. To be able to design new gelators with tailor-made properties, or even to predict gelation behaviour from the molecular structure requires a basic insight into the physiochemical basis for their gelation behaviour, however, such studies have been complicated by the large structural diversity of these systems as well as the structure of the gels itself. Many different techniques have been applied to establish the intermolecular interactions that are involved in self-assembly leading to gelation, to elucidate the structure and morphology of the gel and gel fibres, and to determine the thermotropic and viscoelastic properties.

One important characteristic of gelators is the minimum required amount of gelator to form a gel in a specific solvent, also called the critical gelation concentration, cgc. The cgc consist of two contributions, that is the concentration of material required for the formation of a 3D network (Cagg), and the concentration of gelator molecules that remain in solution (Csol) (Figure 1.3).

Gel fibres are formed via noncovalent interactions and with increasing temperature these aggregates gradually dissolve of the increase of the solubility (Csol). The temperature at which the gel loses its structural integrity is called the gel–sol phase transition (Tgs), and depends on the structure of the gelator, the nature of the solvent and the total concentration of gelator. The Tgs can be determined by various visual inspection techniques, e.g. by the 'dropping ball' technique, bubble motion, or the inverted test tube method. The Tgs corresponds to the temperature at which the gel loses its structural integrity and some of the compound may be aggregated still, however, these aggregates are too small to sustain a network. The Tgs should not be confused with the dissolution temperature or melting temperature (Tm), the temperature at which all aggregates are completely dissolved. At Tm the total gelator concentration is equal to Csol. The solubility curve has to be determined by alternative techniques that either determines Tm for a known total gelator concentration, or that determines the concentration of gelator in solution, e.g. by NMR, or chromato-graphic methods. From measurements of Tgs and Tm in a solvent over a range of concentrations one can draw the phase diagram of that gelator–solvent combination, from which one can read the cgc, Cagg and Csol at each temperature (Figure 1.3).

These phase diagrams can also be used to determine the strength or enthalpy (ΔHm) of the intermolecular interactions in the gel. If it is assumed that the gel–sol transition can be interpreted as dissolution of crystals in ideal solutions, one can determine the melting enthalpy of the gel via the van't Hoff equation (eqn (1.1)):

[MATHEMATICAL EXPRESSION OMITTED] (1.1)

This method is based on the relationship between the logarithm of the concentration and 1/Tm. However, in many studies only Tgs has been determined, which overestimates the dissolved amount of gelator, and leads to too low values for ΔHm. A direct method to determine the melting enthalpy is differential scanning calorimetry (DSC). Unfortunately, the sensitivity of ordinary DSC is often too low for accurate measurements of ΔHm, especially at low gelator concentrations and slow scan rates that are required to maintain dissolution equilibrium during the measurement. When this technique is applied for gels the energy required for the dissolution of the gel fibre is measured and ΔHm can be determined directly.

The dropping ball, bubble motion and inverted test tube methods are also called 'table-top rheology methods', and they already give a clear indication if a gel has been formed or not. However, definite proof has to come from more quantitative studies on the viscoelastic properties of the supposed gels, e.g. by oscillatory rheology experiments. In an oscillatory rheology experiment the sample is subjected to oscillating stress, and the viscoelastic response of the sample is measured in terms of the elastic storage G' and loss moduli G". Gels can behave either as viscoelastic liquids or as viscoelastic solids, which is due to the formation of a highly dynamic or a static network structure, respectively. In general, the dynamic moduli depend on the frequency (time scale) of the measurement. The observed frequency dependence gives insight into the relaxation and lifetime of the bonds between the gelator molecules. If the bonds have a permanent character, only a small frequency dependence is expected and G' [much greater than] G" at all frequencies. This behaviour is characteristic of hard gels containing a static network structure, which do not deform under its own weight. Such hard gels can be considered as true gels according to the definition of Jordon Lloyd. Examples of these systems are gel networks formed by derivatives of compound 1. Another type of gel-like systems are soft-gels, or gellies, which easily deform under their own weight and show gravitational flow. These soft gels are characterised by a typical significant frequency dependency of G' and G", with G' >G" only at high frequencies while at low frequencies (larger time scales) G'< G", pointing to the slow deformation already at low stress. Typical examples of soft gels are solutions of worm-like micelles. Oscillatory rheology experiments are also a reliable method to study the kinetics of gel formation by following G' and G" as a function of time, after having started gel formation. Here, the gel point or gelling time is taken as the time at which G' starts to exceed G".

These rheology studies clearly show that viscoelastic properties and fibre and network morphology are closely related, and therefore the study of the fibre and gel morphology form another essential part of the characterisation of supramolecular gels. Because the structural features of fibres and its network are typically in the range between 5–1000 nm, such study requires suitable direct imaging microscopy techniques, or indirect scattering techniques for such long length scales. Over the years a variety of transmission electron microscopy (TEM) and scanning electron microscopy (SEM) techniques have been applied, which mainly vary in sample preparation procedure. In these techniques the gel fibres are not imaged in their native state and artefacts may arise from the sample preparation procedure, e.g. freezing of the solvent leading to deformation of the gel or precipitation of dissolved gelator fraction (Csol). Indirect methods used to determine fibre morphology are small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS). The particles in the beam are scattered depending on the shape of the fibres and via mathematical treatment of the scattering intensity as a function of the scattering angle, the size and morphology of the gel fibres can be determined. The problem with this method is that some prior knowledge of the size and shape of the gel fibres is required to perform the mathematical treatment. Also, if the sample is not homogeneous the mathematical treatment becomes difficult. Although both direct and indirect methods revealed valuable information on fibre and gel-network morphology, they do not add much insight into the supramolecular arrangement within the fibres.