trans-3-Hydroxy-4-morpholinopiperidine-the pH-triggered conformational switch with a double flip

Derivatives of trans-3-hydroxy-4-aminopiperidine are suggested as potential pH-sensitive conformational switches able to perform two consecutive flips (or flip-flop) when basicity/acidity of solution changes. Such a double switch of conformation was detected by 1H NMR for a model compound-trans-3-hydroxy-4-morpholinopiperidine. A combination of hydrogen bonding and electrostatic/dipole-dipole interactions was suggested for rationalization. Computational studies provided additional insight into the complex intra- and intermolecular forces that determine the relative stabilities of conformers. In similar structures an incorporated trans-3-hydroxy-4-aminopiperidine moiety can serve as a conformational pH-trigger when equipped with substituents designed to perform certain geometry-dependent functions, for example, as cation chelators or as lipid tails.