Multi-step non-covalent pathways to supramolecular systems

Abstract

The spontaneous organization of building blocks into ordered structures governed by non-covalent interactions, or self-assembly, is a commonly encountered pathway in nature to obtain functional materials. These materials often consist of many different components ordered into intricate structures. Compared to this, manmade self-assembled structures are rather simple, since they are usually made by simply mixing the different components together in a solvent. In this thesis, we have used a stepwise approach to obtain supramolecular structures consisting of building blocks that are themselves supramolecular assemblies. In other words, an additional level of hierarchy is obtained, which leads to interesting and sometimes counterintuitive behavior. The focus has been on two supramolecular systems: one based on a globular dendrimer host and complementary guest molecules (Chapter 2 to 5) and one arising from the self-assembly of a telechelic supramolecular polymer (Chapter 6 and 7). The former system consists of the fifth generation urea–adamantyl terminated poly(propylene imine) dendrimer, which is a highly branched molecule. It has 64 bulky adamantane end groups attached via a urea linkage, which causes the dendrimer to be hydrophobic and relatively rigid. Various molecules can interact with this dendrimer host by forming an acid–base interaction of their acetic, phosphonic or sulphonic moiety with one of the 62 tertiary amines of the dendrimer host (i.e. guest–host binding). Additionally, multiple hydrogen-bonding interactions can be formed between the guest and host when the guest molecule is also equipped with a urea moiety. In Chapter 2, we describe the interaction of different monovalent and multivalent guest molecules with this dendrimer host in chloroform solution. The detailed analysis of monovalent ureido–acetic acid guest 1 shows that guest–guest interactions—leading to dimerization of the acetic acid groups and one-dimensional assembly of these dimers via their urea moieties—play an important role in the quantitative description of guest–host binding. The intermolecular guest–guest interactions lower the apparent binding strength of the guest to the host. One way to increase the binding strength is to use multiple copies of the same ureido–acetic acid moiety on one guest molecule. We show that bivalent and tetravalent guest molecules interact five-fold and thirty-fold stronger, respectively, with the dendrimer host compared to their monovalent analogue. A mathematical model was developed to explain the experimental observations. The results show that the concepts of multivalency work in this dendrimer-based system. In Chapter 3, we outline the first stepwise synthetic approach. The guest–host complex comprising the dendrimer host and guest 1 was assembled in chloroform m. Using magic angle spinning nuclear magnetic resonance and atomic force microscopy we show that this complex is also present in the neat phase remaining after evaporation of the solvent. This proved to be crucial to transfer the guest–host complex to aqueous solution. The hydrophilic guest 1 molecules effectively shield the hydrophobic dendrimer host surface. The extent of shielding depends on the ratio of guest to host molecules and greatly affects the structures observed upon dissolution of the neat complexes in water. A shortage of guest molecules yields guest–host complexes in aqueous solution comprising a core of on average three host molecules enclosed by guest molecules. On the other hand, an excess of guest molecules leads to a similar guest–host complex compared to the one found in chloroform solution, consisting of one host molecule surrounded by a corona of guest molecules. The latter guest–host complexes display a counterintuitive behavior upon dilution, described in Chapter 4. As a result of the stepwise preparation method, the complexes are kinetically stable in aqueous solution. The guest molecules plausibly create an entropic barrier around the hydrophobic host molecule causing the solutions to be stable for months. However, dilution lowers the amount of guest molecules on the surface of the host following the common Langmuir adsorption isotherm. This exposes a part of the hydrophobic host surface to the aqueous solution, which causes the guest–host complexes to self-assemble. The resulting supramolecular assemblies become more and more branched upon further dilution, evidenced by the increasing fractal dimension from ~1 to 3. The stepwise non-covalent pathway to obtain the guest–host complexes in aqueous solution, in this case, causes this counterintuitive dilution-induced self-assembly process. In Chapter 5, the same guest–host complexes—above the concentration threshold for their self-assembly—are made bioactive. This is done by synthesizing a bifunctional guest molecule containing both the ureido–acetic acid group as well as an arylpiperazine moiety. The latter is known to interact with a neural (5-HT3) receptor to limit emesis induced by anticancer chemotherapy. The two bioactive guest molecules—one with an aliphatic linker between the ureido–acetic acid group and the arylpiperazine unit, and one with an oligo(ethylene glycol) spacer—have a nanomolar affinity to the neural receptor in vivo. Moreover, a complex consisting of one dendrimer host and a corona of both the bioactive and guest 1 molecules could be obtained in aqueous solution. The second supramolecular system obtained using a multi-step non-covalent pathway consists of different length poly(ethylene glycol) polymers, functionalized on both chain-ends by a hydrophobic aliphatic spacer of variable length and the quadruple hydrogen-bonding ureidopyrimidinone (UPy) unit. The UPy units are known be self-complementary implying they can dimerize. Moreover, urea and urethane moieties close to the UPy motif cause elongated one-dimensional assemblies to be formed. In Chapter 6, it is shown that this supramolecular polymer forms long fibers in the neat state. Moreover, an additional first order phase transition is observed above the melting temperature of the parent poly(ethylene glycol) polymer using differential scanning calorimetry. Upon dissolution of the neat polymer in water its fibrous architecture is partially preserved: a large amount of micelles and single polymer chains coexist with the fibers in solution. The polymer micelles disintegrate below their critical micelle concentration (~10–4 M), while the fibers are stable even at 100-fold lower concentration and at elevated temperatures, which indicates that additional interactions between the supramolecular polymers are present in the fibrous assemblies. At higher polymer concentration (> 5 w/w%) hydrogels are obtained. The onset of gelation is lowest for the supramolecular polymer with the largest hydrophobic part (i.e. UPy unit and the aliphatic spacers) and the shortest hydrophilic part (i.e. the poly(ethylene glycol) polymer chain). Interestingly, slow structural changes were found to occur in the gel state. The materials strengthens in time, which lowers the release rate of a small organic dye (rhodamine B) dissolved inside the hydrogel. Moreover, this structural evolution is detected as a first order phase transition using micro differential scanning calorimetry after one day of ageing, which we attribute to bundling or phase separation of the supramolecular fibrous assemblies in the gel state. The hydrogel material was loaded with a proteinaceous growth factor, which could effectively be delivered to the renal cortex in vivo to intervene in the pathway to inflammation and fibrosis. In Chapter 7, we introduce a microfluidic H-cell to quantify the strength of supramolecular guest–host interactions. Because of the micrometer scale of the fluidic channel, the used aqueous flows stay laminar at all times. This allows the creation of well-defined concentration gradients inside the channel, which could be used to determine the equilibrium binding constant of a guest–host model system. The H-cell was then applied to study the interaction of a single UPy moiety with the different self-assembled structures described in Chapter 6 (i.e. single polymer chains, micelles and fibers). A complementary guest molecule containing a fluorescent dye (rhodamine B) was synthesized and its equilibrium binding strength to the fibers and micelles determined to be 103–104 M–1. Subtracting the non-specific interaction of the rhodamine B moiety with the hydrophobic parts of the supramolecular assemblies, the UPy equilibrium constant is ~5 x 102 M–1. In general, the work in this thesis shows the viability of adopting a stepwise non-covalent pathway to obtain supramolecular structures. Assembly of building blocks that themselves are self-assembled entities yields intriguing behavior of the overall system upon dilution or ageing. In Chapter 8, we reflect in more detail on this stepwise strategy and its implications for the development of future materials.