Competitive H-bonds in vacuo and in aqueous solution for N-protonated adrenaline and its monohydrated complexes

The conformational landscape of the N-protonated form of adrenaline (epinephrine in the U.S.) has been considered at both the B3LYP/6-31G* and 6-311++G** levels, with full geometry optimization in the gas phase and in aqueous solution, using the integral equation formalism for the polarizable continuum model (IEF-PCM). All stable orientations of the two catecholic hydroxy groups as well as the interconversion pathways between them have been taken into account. The dependence of the potential energy profile for the −[NH2CH3]+ group rotation on the catechol ring and side-chain OH group orientation has been also examined. B3LYP/6-31G* stationary points have been confirmed with frequency calculations (at 310 K and 1 atm) allowing thermal corrections and IR spectra to be evaluated. Basis set effects do not alter the relative stability of the various forms that is maintained also when MP2 correlation corrections are included. The role of the internal structures either embedding in aqueous solution the conformers kept rigid at their in vacuo geometries or allowing the structure to relax has been examined at the IEF-PCM/B3LYP/6-31G* and 6-311++G** levels and compared to the IEF-PCM/MP2/6-31G* results. In vacuo the G1 conformers are favored with respect to the T and G2 ones, while in water the stability ordering changes, T becoming significantly more stable than both gauche forms. This occurs even for the gas-phase structures, including or not thermal corrections. The addition of a single water molecule to N-protonated adrenaline caused the intramolecular H-bond within the side chain to weaken till formation of two H-bonds with water. This fact, coupled to the strain relaxation, further stabilized the G1 and T conformers. The maximum intensity of the IR spectra increases in solution, especially for monohydrated adducts, where a significant red shift in the vibration of the NH involved in a H-bond to the water O is found.