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

2,4,6‐Trihydroxybenzoic acid (FA) is the carboxylic acid of phloroglucinol and, in turn, the parent compound of many biologically active compounds. The biological activities of FA are “extreme” among trihydroxybenzoic acids (e.g., lowest antioxidant activity, highest toxicity toward crustaceans). A complete MP2/6‐31++G(d,p) conformational study in vacuo shows that the lowest energy conformers contain two intramolecular hydrogen bonds between the COOH function and the two ortho phenolic OH, with the Z form of COOH preferred over the E form. Comparisons with conformers in which the H‐bonds are removed enable fairly reliable evaluations of their energy, because of an off‐plane shift of COOH on H‐bond removal, decreasing the effects of lone pair repulsion. Comparisons with the other hydroxybenzoic acids (extensively calculated in vacuo at the same level of theory) suggest that FA has the strongest intramolecular H‐bonds. PCM calculations of FA in water solution show the same sequence of relative stabilities as in vacuo, with narrower differences because of the greater solvent stabilization of higher energy conformers. Calculations of adducts with water molecules H‐bonded to different donor–acceptor centers of FA show the preferred arrangements of water molecules around the different regions of FA and confirm that the stronger intramolecular H‐bonds are not broken on competition with the possibility of formation of intermolecular H‐bonds. HF/6‐31++G(d,p) calculations of adducts, in which the FA molecule is completely surrounded by water molecules, show that 14–16 water molecules (depending on the FA conformer geometry) realize arrangements corresponding to a presumable first solvation layer, with all the water molecules directly H‐bonded to donor–acceptor centers of FA or bridging water molecules directly H‐bonded to them. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010