Controlling the Assembly of Ureido‐Pyrimidinone Supramolecular Monomers by Tuning the Hydrophilic‐Hydrophobic Balance

Understanding the self-assembly of supramolecular monomers in water is essential to develop responsive and bioactive biomaterials. In this work, a series of water-compatible ureido-pyrimidinone (UPy) derivatives differing in the length of the oligo(ethylene glycol) chain and of the alkyl-urea spacer are prepared. The self-assembly behavior of each monomer is elucidated in water by means of experimental techniques and computational molecular modeling, unveiling the importance of the monomer hydrophilic-hydrophobic balance in the self-assembly properties and morphology of the resulting supramolecular polymers. Even though the increasing size of the alkyl-urea spacer is shown to foster both the UPy dimerization and the pi-pi stacking of the dimers, molecular dynamics simulations highlight a competitive intramolecular interaction between the UPy core and the lateral urea moiety, leading to the formation of sheet-like structures rather than one-dimensional supramolecular polymers in water. The findings of this work highlight the importance of monomer design on the self-assembly properties of UPy systems, paving the way towards the development of novel supramolecular biomaterials with tuneable properties.