Submitted to: Journal of Molecular Structure (Theochem)
Publication Type: Peer reviewed journal
Publication Acceptance Date: 7/27/2004
Publication Date: 9/1/2004
Citation: Hu, X., Shelver, W.L., Wettstein, G.W., Gholami, K., Shelver, W.H. 2004. Studies of intramolecular hydrogen bonding in protonated and non-protonated hexahydrophyridinobenzodioxins. Journal of Molecular Structure (Theochem)686:7-14. Interpretive Summary: Compounds which contain fused six-member rings (for example, hexahydrobenzopyridinobenzodioxane) are of considerable synthetic and theoretical interest owing to their biological and chemical properties. Some of these compounds are the core structures for drugs to treat high blood pressure. These compounds can exist in two different stereochemistry (cis and trans). The cis form can exist in two additional conformers. An instrumental structure identification indicates the hexahydrobenzopyridinobenzodioxane we synthesized only exists in one conformation. The authors used calculations to decide which form was the most stable and would be expected to be detected by experimental measurement. The authors compared a series of calculations ranging from relatively simple, that could be carried out on a PC, to very complex that took several days on a cluster of PC's with super computer capability. To our knowledge, this is the first report of a theoretical calculation study carried out for two fused six-member rings. The more complex calculation system predicts more accurately the instrumental measurement result. The results will help scientists make better predictions of biological systems.
Technical Abstract: The conformational stability of hexahydropyridobenzodioxin and related derivatives in both protonated and non-protonated forms have been investigated by means of ab initio molecular orbital methods as well as semiempitical AM1 and PM3 methods. One of the cis conformers (cis2e) has been found to be most stable due to the formation of an intramolecular hydrogen bond, other conformers including the trans isomer cannot form this interaction but are of different stability because of the orientation of the polar oxygens and the nitrogens. The effect of the intramolecular hydrogen bonding on the stability of hexahydropyridobenzodioxin and its methylated derivatives has been examined using various basis sets levels. In protonated form, both the semiempirical and ab initio calculations give excellent agreement in energetic order; however, different orderings of conformer stabilities are observed by different computational methods in non-protonated form. The results provide insight into the intramolecular hydrogen bonding in computational studies of biologically important molecules.