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

ABSTRACT 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 π–π 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.