Supramolecular perspectives in colloid science
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- Cohen Stuart, M.A. Colloid Polym Sci (2008) 286: 855. doi:10.1007/s00396-008-1861-7
Supramolecular chemistry puts emphasis on molecular assemblies held together by non-covalent bonds. As such, it is very close in spirit to colloid science which also focuses on objects which are small, but beyond the molecular scale, and for which other forces than covalent bonds are crucial. We discuss in this review the preparation and properties of new colloidal systems which borrow on the one hand from classical topics in colloid science, such as micellization, and on the other hand from concepts in supramolecular chemistry, such as reversible supramolecular polymers.
Chemistry is concerned with the question how atoms combine into structures that eventually become materials with certain properties and functions. In particular, synthetic organic chemistry developed into a highly refined art to make molecules, multi-atomic particles held together by covalent bonds. However, one molecule does not yet make a material. Between molecules, weaker, non-covalent interactions play their part in defining the structure and dynamics of systems. Employing such interactions to make molecular assemblies with a significant lifetime, so that one can see them as a kind of ‘giant molecule’, might be considered as an extension of classical synthetic chemistry into the realm of ‘supermolecules’. Hence the term ‘supramolecular chemistry’ was coined by Jean-Marie Lehn to denote this particular scientific endeavor . Supramolecular chemistry has met enormous enthusiasm; it is almost the latest paradigm in synthetic chemistry.
How does this relate to colloid science? Colloidal systems are often composed of multimolecular particles as well, e.g., emulsion droplets or latex particles consist of many molecules which stay together simply because they are insoluble in the continuous phase. However, these particles do not really qualify as supramolecular assemblies in the sense alluded to above. A different class of colloidal systems is that of the association colloids, in which molecules reversibly associate into multimolecular particles with a well-defined size and structure. The classical example is that of soap micelles: the amphiphilic soap (surfactant) molecules stay together because they have an insoluble part (‘tail’) which tends to avoid contact with the solvent, but they also have a soluble moiety (‘head’) which has to remain well solvated. The compromise is a structure which shields the tails from the solvent so that its area per unit mass is large, and this implies either small particles or thin threads (spherical or cylindrical micelles) or thin sheets (lamellae), or hybrids between these (bicontinuous structures). In a way, surfactant micelles, because they have a (thermodynamically) defined size and average shape, can be considered as supramolecular entities. Since they organize themselves spontaneously, they are sometimes referred to as ‘self-organised nanosystems’. Micellar systems have since long been studied extensively within the colloid science community , so that it is not too far-fetched to say that colloid scientists were involved in supramolecular chemistry ‘avant la lettre’.
A more interesting question is: can we find inspiration from supramolecular chemistry to develop colloid science? I think we certainly can, because (a) supramolecular chemistry can provide us with new kinds of colloidal objects and because (b) supramolecular objects can induce new kinds of surface forces. In the remainder of this review, I will discuss examples illustrating this claim.
Thermodynamic picture of micellization
If this were the whole picture, particles, once formed, would tend to grow to very large sizes (because the free energy would continue to decrease with size). In fact the two terms just mentioned are the ingredients of classical nucleation theory . However, free growth is prohibited by the lyophilic moieties (head groups) of the molecules: the free energy increases as soon as these loose contact with the solvent by being ‘buried’ in the domain of insoluble parts. Hence, aggregate growth in all three spatial dimensions has to stop. This leaves two possibilities: growth has to stop altogether (we then get spherical micelles), or it must be limited to one dimension (cylindrical micelles) or two dimensions (lamellae) . Due to the balance between lyophobic attraction and lyophilic repulsion, the free energy as a function of aggregation number (or of aggregation number per unit length or area) has a distinct minimum, which limits the extent to which size fluctuations can occur.
Reversible supramolecular polymers
The case of cylindrical micelles is interesting. Long cylindrical micelles share many properties with polymers because of their ability to undergo thermal shape (bending) fluctuations. The typical difference is, of course, that the covalent bonds in an ordinary polymer are extremely long-lived, whereas these in a cylindrical micelle break and form rapidly at experimental time scales, which has consequences for their rheological behavior. Hence, these micelles can be seen as part of a special class of ‘reversible supramolecular polymers’ (RSP’s), and quite some research has been devoted to them to understand their static and dynamic properties [5, 6]. Cylindrical surfactant micelles are not the only possible kind of RSP; there are many more. For example, in almost all living creatures, the protein actin occurs; it forms filamentous assemblies that are part of the cytoskeleton, the structure responsible for the cell’s mechanical performance . In a biomimetic approach, we have recently prepared a new protein polymer which can be triggered to form very similar fibrils; this polymer will be discussed later in this review.
However, one can do more. The ingredients discussed above can be used as the starting point for assembling new colloidal species with increased complexity. As explained, poor solubility and a stop mechanism are necessary, but also sufficient ingredients of a self-assembly process. When we consider solubility, we usually think of a single molecular species in a solvent: poor solubility then means that the solute segregates from the solvent. However, solubility may also be affected by attraction between two soluble species. What options do we have here?
The key issue is that we can have poor solubility with pairs of oppositely charged macromolecules. This might be employed to make films and capsules. The now very popular ‘layer-by-layer’ method  aims at doing so, and indeed works provided redissolution upon exposure to a polyelectrolyte solution is slow or even totally suppressed so that it cannot occur during a dipping cycle. Typically, polymers with strong ionic groups (e.g., sulfonates and quaternary ammonium groups) are good at this, and backbone hydrophobicity also helps. In other cases, however, redissolution does occur .
Complex coacervate micelles
What about a stop mechanism? This is straightforward: an uncharged block or graft added to a charged polymer can very well fulfill this role, provided it has no tendency to enter the dense complex phase. Given the general tendency of polymers to avoid mixing unless there is a specific attraction, this is very unlikely to happen. Hence, we can make micelles with a pair of oppositely charged macromolecules, at least one of which carries a water-soluble, non-ionic block . Such micelles are now known for about 12 years, in many variations. They are usually spherical, having radii varying between 10 and 30 nm, and typically consist of a relatively dense core which contains the insoluble polyelectrolyte complex, surrounded by a more dilute corona of swollen neutral and hydrophilic chains; we denote them accordingly as Complex Coacervate Core Micelles or C3M’s. Other terms used are ‘PIC micelles’ (polyion complex micelles) or ‘BIC’s’ (‘block ionomer complexes’). In several respects, they are very similar to the more familiar micelles formed by amphiphilic diblock copolymers such as, e.g., poly ethylene oxide–b-polystyrene. New features are, however, that they are sensitive to solution parameters that affect the ionic complex, such as salt concentration and pH, and that they often respond reversibly to changes in polymer composition: they appear near-stoichiometric conditions, but disappear upon leaving the near-stoichiometric range, just like the complex coacervates do. Micelles of this kind are highly interesting candidates for targeted drug delivery to tumors, since they have just the right size to benefit of the Enhanced Permeability and Retention (EPR) effect that occurs in tumor tissue due to the leaking of blood vessels, and they can be loaded with various anticancer drugs .
The polymers used were polyacrylate-b-polyacryl amide (PAA42-b-PAAm417) and poly ethylene oxide-b-poly-N-methyl-2-vinylpyridinium iodide (P2MVP42-b-PEO446), mixed so that f= 0.5, in dilute aqueous solution. First, cryo-TEM images (Fig. 5) show a mixture of circular and elliptical objects, as if one is looking at a collection of randomly oriented discs. Usually, the corona is invisible in such pictures so that, probably, we deal with disc-shaped cores.
This is confirmed by SANS data (Fig. 6). A fit with a shape factor for ellipsoids with main axes of 18 and 2.5 nm, respectively, is the only one giving satisfactory agreement (see residuals), without having to assume very exotic polydispersities which are not seen in cryo-TEM. Moreover, the sizes found closely match those of the images.
So far, this only tells us we have a non-spherical core shape, which would be very unlikely without some sort of symmetry breaking tendency. A more direct piece of evidence that the corona is not mixed comes from NMR-NOESY experiments. In such experiments, a particular nuclear resonance can be observed by irradiation of a nucleus which is chemically different but spatially close: magnetization is then transferred by coupling between the spins. As a result, the 2D NOESY spectrum of true mixtures of two polymers shows off-diagonal peaks, whereas such peaks would be absent for a demixed corona. Both cases do indeed occur (Fig. 7): polyacryl amide and poly glyceryl methacrylate mix (Fig. 7, left diagram), but poly acrylamide and poly (ethylene oxide) do not (Fig. 7, right diagram), which strongly supports the Janus hypothesis.
As to the dynamics of formation, there is a fundamental difference between two-component and one-component micelles. As is often the case in a colloid preparation method, one starts out with a soluble precursor that is driven into a colloidal state by a change in solubility due to, e.g., chemical reaction, temperature change or solvent change. Polymer micelles are usually prepared by a ‘solvent quench’, i.e., a rapid change in solvent composition. When this is done with a conventional amphiphilic copolymer, the one block which becomes insoluble will collapse (which it can do without any other polymer molecule around) after which it aggregates into a multimolecular particle. Only the rate of the latter process is concentration dependent; in dilute solutions, the unimolecular collapse process will always be finished before any aggregation takes place. As a result, the formation of micelles proceeds rather smoothly, even though quite some shape variation is possible . With C3M’s this is completely different. Here, the first step is always intermolecular, no unimolecular collapse is possible. What then happens depends strongly on composition. At compositions around f = 0.5, the random encounters between molecules of opposite charge initially leads to a dense, insoluble network that can subsequently rearrange into micelles. The rearrangement process requires the multiple breaking and forming of ions pairs which can be very slow due to the associated energy barriers , or may be even blocked altogether. At compositions far from f = 0.5, the build up of multimolecular species is much more gradual. Hence, the rate at which components are mixed has great consequences for the kinetic pathway taken by the system and, depending on relaxation rates, may sometimes lead to equilibrated structures, sometimes to frozen particles . One can therefore say that these systems take an intermediate position between the ‘lyophobic’ and ‘lyophilic’ classes traditionally distinguished in colloid science.
What other options do we have? A diblock copolymer is very effective in providing a stop mechanism. Hence, this ingredient cannot be missed. However, for the other ingredient(s) one has quite some freedom. Simple polyelectrolytes of varying length have been used, but also proteins (enzymes) , ionic surfactants , and inorganic particles have been successfully incorporated. Systems composed of an ionic surfactant and diblock copolymers deserve some attention, since they can be considered as ‘micelles within micelles’ that is, an example of hierarchical structures. Low MW surfactant micelles are very dynamic, and therefore, the compound micelles based on them are equilibrium systems; their structure is entirely independent of sample history.
Supramolecular surface forces
A central concern of colloid science is with forces between lyophobic colloidal particles. These can be electrodynamic in origin and arise from the body of the particles (van der Waals forces, dispersion forces), but quite often they must be assigned to properties of the particle/medium interface (true surface forces). As such, they are the result of all the interactions between the particle and the surrounding medium, including various solutes. The well-known double-layer interaction is an example that has been studied at length ; and also steric and depletion forces induced by soluble polymers have received much attention . However, there are many more cases where subtle processes in solution show up as colloidal interactions or surface forces. We consider some cases where self-assembling objects are involved.
One example which has been discussed from a general theoretical viewpoint is that of RSP’s between surfaces . RSP’s come in two classes: ‘non-directional’ and ‘directional’. The first class forms structures which possess inversion symmetry: the chains do not have a ‘head’ and a ‘tail’ or a ‘+’ and ‘−’ end. The second class does, because all the units have head and tail. The RSP’s based on coordination complexes clearly belong to the former class; an example of the former would be a single-stranded DNA chain the ends of which (when read in the same direction) are complementary. As can be shown, the non-directional RSP’s, when end-attached to identical surfaces, always generate attraction, whereas the non-directional ones can generate repulsion. Compatible mixtures of the two can even generate non-monotonic interactions. One example of attraction in the case of a non-directional RSP has been recently reported , but the ‘directional’ case has not been realized yet.
A second example is that of solutions of self-assembling species interacting with a solid/liquid interface . A third example is a solution of self-assembling species close to a phase separation boundary. Here, the presence of a surface may induce a ‘precursor’ of the incipient phase when it prefers solute over solvent. If this occurs for liquid/liquid phase separation, one could refer to it as capillary condensation, and the ensuing force is a capillary force. A beautiful example was recently reported  and it seems that many more examples lie awaiting us in multicomponent complex fluids. They definitely deserve investigation, particularly from a dynamic point of view. Innovations from the side of synthetic chemistry will bring in new compounds that might induce such surface forces.
Where can we go from here?
Let us discuss some ideas. Copolymers with a diblock structure tend to primarily form micelles, but copolymers with a triblock sequence (sometimes called telechelics) can do more. In particular, they can make networks of micelles. In the latter category we find, e.g., the associative thickeners based on polyethers (PEO) with insoluble (alkyl) end groups widely applied in water-based paints. Following up on this, one would expect that telechelics with charged end blocks would also be able to form similar networks in the presence of a stoichiometric amount of oppositely charged macroions. Remarkably, no literature reports on such networks can be found in the literature so that we have started an investigation in this direction.
Colloid Science, with its roots in Physical Chemistry, and Supramolecular Chemistry, with its firm basis of synthetic organic and organometallic chemistry can mutually benefit a lot. The appearance of new structures and ways to tune and manipulate structures enriches both fields. Promising developments are to be found also in the realm of biopolymers, where the repertoire of possible conformations and internal interactions is so much larger than that for most synthetic polymers, and rules of thumb developed for simple polymers do not apply. Hence, nanoassemblies of biopolymers (and hybrids of these with synthetic compounds) are a great target for future work.
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