Interplay of intra‐ and intermolecular H‐bonds for the addition of a water molecule to the neutral and N‐protonated forms of noradrenaline

Abstract

ABSTRACT:The conformational flexibility of noradrenaline in its N-protonated and neutral forms was considered at the Hartree-Fock (HF)/6-31G * level, taking into account the orientation of the two hydroxy groups located on the catechol ring and the interconversion pathways between their stable arrangements. The difference in stability among the various forms of N-protonated noradrenaline was maintained including either more diffuse functions on the heteroatoms or Møller-Plesset second order (MP2) correlation corrections. The embedding in aqueous solution, in the polarizable continuum model framework, of the conformers kept rigid at their in vacuo geometries favored the T conformers with respect to the G ones at the HF level (for neutral noradrenaline at the MP2 level as well). The addition of a single water molecule to noradrenaline (either N-protonated or not) caused the intramolecular H-bond within the side chain to weaken until formation of one or two intermolecular H-bonds with water. This fact, coupled to the intramolecular H-bond strain relaxation, further stabilized the G1 and T conformers. Continuum solvation of the hydrated clusters of neutral noradrenaline favored significantly the T· · ·water adducts at the HF level, but only slightly at the MP2 level, because of their large energy gap in vacuo with respect to G1· · ·water, even enhanced by MP2 geometry optimizations. The dependence of the potential energy profile for the NH 2 group rotation on the catechol ring and side chain OH group orientation was examined in noradrenaline and compared to the trend shown by dopamine. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem 90: 641-656, 2002

A computational study of the carboxylic acid of phloroglucinol in vacuo and in water solution

“…The relative energy trend does not differ significantly from in vacuo, but the spacing between relative energies narrows, so that FA‐2 and FA‐3, that are not populated in vacuo, have nonnegligible population in water solution and the relative energy of the highest energy conformer (FA‐6‐w) is 4.971 in solution. This is consistent with the general observation that the solvent stabilization is greater for conformers that are less stable in vacuo 68. The stabilization extent is also related to the number of free OH (that can form intermolecular H‐bonds with water molecules) and to the types of intramolecular H‐bonds.…”

“…PCM calculations were performed for FA in water solution, with full reoptimization because this ensures a more realistic and physically consistent description of the solvation phenomenon and a better agreement with experimental results 67. Table VIII reports the relative energies and populations of the conformers having nonnegligible population in solution, the relative free energy in solution (Δ G soln ), the solvent effect (Δ G solv ; Δ G solv = G soln − E vac 68) and its electrostatic (Δ G el ) and nonelectrostatic (Δ G non‐el ) contributions (the latter including cavitation, dispersion, and repulsion terms 68).…”

“…Given the practical unaffordability of MP frequency calculations, the calculations for the prediction of p K a were performed at DF+ level. An additional complication stems from the fact that the PCM model is unable to take into account the solute–solvent H‐bonding 71, 75, which affects the computational evaluation of G aq o terms. Different options were tested to try and minimize the impact: the consideration of a separate sphere for acidic H atoms on building the PCM cavity 52(b); the increase of the radius of the two O atoms of the COO − function in FA − 76; the consideration of adducts containing one or more explicit water molecules H‐bonded to the donor/acceptor centers, so as to incorporate the stronger solute–solvent H‐bonds 67, 70.…”

“…The consideration of adducts with explicit water molecules is important when the solute molecule can form H‐bonds with water molecules, as these bonds constitute a stronger molecule–water interaction than that viewed as “bulk solvent” and cannot be taken into account by the PCM model 75. The energy of the interaction between FA and the n water molecules in an adduct ( E FA‐aq ) is calculated as follows: …”

“…The energy of the water–water interactions ( E aq – aq ) is evaluated through a single‐point calculation on the water molecules arranged in the same way as in the adduct, but without the FA molecule 68(b)). Both E adduct and E aq – aq are corrected for BSSE.…”