Intramolecular Hydrogen Bonds in Hydroxy Acids.

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Gamma-hydroxybutyric acid is one of the few substances, which are able to pass the barrier between blood and brain. This physiological property has earned gamma-hydroxybutyric acid the abbreviation "GHB". It occurs naturally in the mammelian brain, where it is synthesized and released by specific neuronal circuits, which possess neuromodulatory functions. The synthesis in the brain involves gamma-aminobutyric acid (GABA) or 1,4-butanediol as precursor substances. GHB can also be synthesized in the mammelian liver from gamma-butyrolactone. GHB is able to substitute ethanol during ethanol withdrawal and has been used in the treatment of alcohol dependence as well as narcolepsy. In the recent years, however, it has also been used as an ingredient of party drugs.

(structure1 with H-bond) (structure2 with H-bond) (structure3 with H-bond)

Regarding intramolecular interactions, three symmetry-unique conformers have to be named in first place, all of which form a hydrogen bond (CO)O-H···O-H. These three conformers are shown on top of this paragraph in the order of their energies. The most stable (A) is of the envelope-type: the COOH-group, the carbon atoms alpha and gamma, and the aliphatic OH-group are located approximately in one common plane, whereas the carbon atom beta sticks out of that plane. The two other conformers (B and C) have a kind of distorted boat form and differ only in the orientation of the OH-group. The hydrogen bond in these two is weaker than in A, which can already be seen from the overlap in the fused sphere models. A network of hydrogen bond preserving reactions exists between these three conformers and their enantiomers (a, b, c), which is shown in the following scheme.

(global minimum) As in the other hydroxy and amino acids, none of these H-bonded conformers is the global minimum of the potential energy surface due to the energetically unfavourable trans-orientation of the COOH-group. A numerical estimate for GHB gives a cis-trans energy difference of 35.3 kJ/mol and H-bond stabilization energies of 34.9, 23.9, and 23.5 kJ/mol, respectively. The global minimum is shown at the beginning of this paragraph. In it, the COOH-group is almost coplanar with the carbon atoms alpha and beta, carbon atom gamma is located out of that plane, and the aliphatic OH-group is oriented towards the carbonyl oxygen atom. The H···O-distance in the resulting O-H···O=C-interaction is slightly longer than in the corresponding conformer of beta-hydroxypropionic acid, namely 2.33 Å. According to the electron density between the groups OH and CO, this interaction is not a hydrogen bond but a electrostatic attraction.

(structure1 with O-H...O=C-bond) (structure2 with O-H...O=C-bond) In contrast, the same interaction O-H···O=C forms a hydrogen bond in four other symmetry-unique conformers, namely the two shown next to this paragraph and their analoga with trans-orientation of the COOH-group. This hydrogen bond is weak, however, with bond orders between 0.025 and 0.030.

(structure3 with O-H...O=C-bond) A stronger form of this O-H···O=C hydrogen bond (with a bond order of 0.044) is formed in another conformer, which is shown next to this paragraph. The geometry of this conformer can be described as a distorted envelope-type with carbon atom gamma out of the plane. In this case, an energetical effect of the hydrogen bond cannot be ruled out, since this conformer is third in energy (out of a total of 66 symmetry-unique conformers in the quantum chemical ab initio potential energy surface).

Furthermore, three conformers with a cis-orientation of the COOH-group have to be mentioned, in which a weak hydrogen bond O-H···(CO)O-H is formed. These three conformers are shown at the end of this paragraph in the order of their energy. The one shown in the center also has a high-energy analog with trans-orientation of the COOH-group.

(structure1 with O-H...O-H-bond) (structure2 with O-H...O-H-bond) (structure3 with O-H...O-H-bond)

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