The self-complementary hydrogen bonding ureido-pyrimidinone (UPy) motif is widely used in the design of supramolecular polymers because of its high dimerization constant. Lateral aggregation into fibrous structures is achieved by the addition of urea functions close to the UPy end group of low-T g oligomers, yielding supramolecular thermoplastic elastomers. The rate of fiber formation is critically dependent on the substituent at the five- and six-positions of the UPy unit. Here the aggregation behavior in the solid state is disclosed for a series of molecules with the commonly used methyl, the optically pure (S)-2,7-dimethylheptyl and (S)-1-methylpropyl, and the racemic 1-ethylpentyl group at the six-position. The rate of nanofiber crystallization from the melt was investigated with a variety of techniques, including SAXS, WAXS, AFM, DSC, IR, and CD spectroscopy. As a result, the different stages involved in the nanofiber formation were elucidated. The nanofiber formation is a hierarchical process starting from the phase-separated melt with the dimerization of the UPy-units. For the lateral aggregation into high aspect nanofibers, both a nonsubstituted five position and urea functionalities are required. The nanofiber formation is the result of 1D stack formation accompanied by secondary nucleation of multiple stacks. The stack-to-stack distance within a nanofiber is dependent on the size of the UPy-substituent, which demonstrates that the substituents are in-between the stacks in the nanofibers. The results also demonstrate that stack and nanofiber formation is slowed down and suppressed by a branching of the six-substituent close to the UPy motif, whereas the presence of stereochemical isomers further suppresses this aggregation from the melt. These detailed insights into the kinetic behavior of nanofiber formation pave the way to create adaptable supramolecular materials.

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Ureido-pyrimidinone (UPy) dimers substituted with an additional urea functionality self-assemble into one-dimensional stacks in various solvents through lateral non-covalent interactions. (1)H NMR and DOSY studies in CDCl(3) suggest the formation of short stacks (<10), whereas temperature-dependent circular dichroism (CD) studies on chiral UPy dimers in heptane show the formation of much larger helical stacks. Analysis of the concentration-dependent evolution of chemical shift in CDCl(3) and the temperature-dependent CD effect in heptane suggest that this self-assembly process follows an isodesmic pathway in both solvents. The length of the aggregates is influenced by substituents attached to the urea functionality. In sharp contrast, UPy dimers carrying an additional urethane group do not self-assemble into ordered stacks, as is evident from the absence of a CD effect in heptane and the concentration-independent chemical shift of the alkylidene proton of the pyrimidinone ring in CDCl(3).

In the past decade, significant progress has been made in the field of biomaterials, for potential applications in tissue engineering or drug delivery. We have recently developed a new class of thermoplastic elastomers, based on ureidopyrimidinone (UPy) quadruple hydrogen bonding motifs. These supramolecular polymers form nanofiber-like aggregates initially via the dimerization of the UPy units followed by lateral urea-hydrogen bonding. Combined kinetic and thermodynamic studies unravel the pathway complexity in the formation of these polymorphic nanofibers and the subtlety of the polymer’s design, while these morphologies are so critically important when these materials are used in combination with cells. We also show that the cell behavior directly depends on the length and shape of the nanofibers, illustrating the key importance of macromolecular and supramolecular organization of biomaterials. This study leads to new design rules that determine what factors are decisive for a polymer to be a good candidate as biomaterial.