Studies on the Hydrogen Bonding of Organic Chemicals

Abstract

Hydrogen bonding is a very important topic in pharmacology, used in docking studies and Quantitative Structure-Activity Relationships (QSAR). While one hydrogen bond is weak, a set of hydrogen bonds provides the major force that binds a ligand and its docking site. This thesis is based on my own experiments and updates some preliminary results from my supervisor’s former student Rutian Jin. Firstly the literature is reviewed for inter- and intra-molecular hydrogen bonding and the forces between the bonded atoms. An empirical rule proposed by M. Etter is presented: intramolecular hydrogen bonds forming six-membered rings are preferred. Finally the technique used in determination of actual structure in crystals is described. Next are the experimental results from my entire study period. Crystal structure determinations are reported for three molecules where intramolecular hydrogen bonds could create six-membered rings. Surveys of the Cambridge Structural Database (CSD) are presented. The previous general survey of the frequency of occurrence and the geometrical effects of hydrogen bonded six-membered rings has been updated. Hydrogen bonding in analogues of the new structures is analysed. The numbers of independent hydrogen bonds formed by four pharmaceutically acceptable ions are tabulated. Finally come some conclusions about my findings. As predicted, in 2-hydroxy-4,6-dimethoxyacetophenone and most analogues in the CSD strong intramolecular O-H---O hydrogen bonds create six-membered rings, with some correlation between strength of this hydrogen bond and electronic effects of ring substituents on the OH and C=O groups. Neither N-hydroxymethyl- nor N-3-hydroxypropylphthalimide form 6-membered rings by means of intramolecular hydrogen bonds. Even with three hydrogen bond acceptor atoms instead of one, the nitrate ion tends to accept no more hydrogen bonds than chloride. The ammonium ion commonly donates one hydrogen bond per hydrogen atom. With both donor and acceptor functionality the dihydrogen phosphate ion forms a variable number of independent hydrogen bonds.