We have investigated at the atomic level amide-based rotaxanes set in motion in four different solvents, namely, ethyl ether, acetonitrile, ethanol and water. In three non-aqueous solvents, shuttling of the macrocycle between two binding sites separated by a free-energy barrier is coupled with a conformational change and rotation, driven primarily by hydrogen-bonding interactions. The mechanism that underlies the shuttling is completely altered when the non-aqueous solvent is replaced by water. In aqueous solution, hydrophobic interactions chiefly control shuttling of the rotaxane, leading to a sharp decrease of the free-energy barrier, thereby speeding up the process. The binding sites and the reaction pathway describing shuttling vary significantly in water compared with in the other three solvents. We found that the high polarity, the hydrogen-bond donor and acceptor ability, and the minimal steric hindrance of water conspire to modify the mechanism. These three physicochemical properties are also responsible for the lubrication by water. That water completely changes the mechanism underlying the shuttling of rotaxanes, is addressed for the first time in this study, and provides valuable guidelines for the de novo design of molecular machines.
†Electronic supplementary information (ESI) available: Methods, structure of the rotaxane, free-energy calculation characterizing the isomerization of the ring-like molecule, free-energy landscape for the translation and conformational change of the ring in the rotaxane in vacuum, representative three-dimensional arrangements of the rotaxane in vacuum, rotation of the macrocycle along with translation, rotation of the terminal group of the dumbbell-like molecule accompanied with other movements in the rotaxane, one-dimensional free-energy decomposition, committor analysis, hydrogen bond analysis, boat–boat transformation of the macrocycle during the shuttling, solvent-accessible surface area (SASA) of the chain-like molecule along the transition coordinate in different solvents. Simulation parameters. See DOI: 10.1039/c7sc01593c