trans-2-Aminocyclohexanols as pH-Triggered Molecular Switches

Our group studies molecular switches that change their shape dramatically within a specific pH range, making them useful for various applications. One potential application of these switches is targeted drug delivery. Molecular switches can be the lipid-like membrane components for drug-encapsulating liposomes. When the liposomes encounter an acidic environment, such as cancerous tumors, the molecular switches undergo a conformational change that disrupts the liposomes and releases the drug. This necessitates finding switches that change conformation drastically and within a specific pH range. Trans-2-aminocyclohexanols act as conformational switches that reversibly change the relative orientation of substituents. We study new 4,5-diacyloxy derivatives that have a different set of substituents compared to previous research. These molecules have two chair conformations in a fast equilibrium. In a neutral environment, the predominant conformer has two acyloxy groups in equatorial positions with an amino group and hydroxyl in axial positions. In presence of acid, the amino group is protonated and forms an intramolecular hydrogen bond with the adjacent hydroxyl, bringing both groups closer together in equatorial positions, and forcing the acyloxy tails into axial positions. We are researching the impact of different amino groups on the acidity required for the conformation switch. The equilibrium between conformers is gauged by nuclear magnetic resonance (1H-NMR). The proton-proton coupling constants are strongly dependent on the conformation. When a substituent is axial, the signal of the geminal H is narrow in the range of ~10Hz. The equatorial conformation results in a broad signal of ~25Hz. Ongoing research involves studying the conformationally locked models to find the extrema of signal width and an estimation of an equilibria position from the observed signal widths for the switches over a range of acidities