Abstract
The self-assembly of molecularly interlocked molecules offers new opportunities for creating bioactive molecules for applications in medicine. Cooperative capture synthesis of heterorotaxanes in water is an attractive methodology for developing multifunctional supramolecular imaging agents or drugs, but derivatizing the rotaxane scaffold with biologically active vectors like peptides and proteins, or reporter probers like radioactive metal ion complexes and fluorophores, requires the installation of reactive functional groups. Here, we explored the chemical scope of β-cyclodextrin (β-CD) derivatization on the cucurbit[6]uril (CB[6])-mediated cooperative capture synthesis of hetero[4]rotaxanes with the objective of identifying which reactive groups can be used for further functionalization without compromising the efficiency of rotaxane synthesis. Nine β-CD derivatives featuring an electrophilic leaving group (tosylate), aliphatic amines, a carboxylic acid, aliphatic azides, anilines, and aryl isothiocyanate were evaluated in the synthesis of hetero[4]rotaxanes. Experimental measurements on the kinetics of rotaxane synthesis were combined with detailed computational studies using the density functional theory to elucidate the mechanistic pathways and rate determining step in the cooperative capture process. Computational studies on the structure and bonding also revealed why intermolecular interactions between the β-CD and CB[6] macrocycles improve the rate and efficiency of rotaxane formation through cooperative capture. Understanding the mechanistic details and synthetic scope will facilitate broader access to functionalized hetero[4]rotaxanes for applications in biomedicine and beyond.
d’Orchymont, Faustine