Theoretical Study On Tautomerism And QSAR Of Multi-carbonyl Compound

The thesis is about theoretical calculation on tautomerism and the relationship between the activity and structure of multi-carbonyl compound. There are four main parts:In the first part, the calculations were performed at ab inito level for the possible tautomers of 2-acetyl-cyclo-1,3-dione derivatives. Both the influences of the ring structure and solvent effect on the relative stability of the tautomers were examined. 12 kinds of derivative from 2-acetyl-cyclo-1,3-dione with different rings structure were studied. The influences of the saturation degree of rings, the ring size, the heteroatoms in the ring and the polarity of solvent on the relative stability of the tautomers were discussed. The reliability of theoretical calculation is verified by comparing the calculated results with the searching results from Cambridge Structural Database. It is demonstrated that unenoliazted isomers possess high energy because of the absence of intramolecular hydrogen bond, and the negative charges on carbonyl oxygen are increased due to the electron-donating effect of the heteroatom in the ring, which is in favor of the stability of the corresponding exocyclic enol-tautomer. In order to express the aromaticity of some compounds quantitately, we calculate Nucleus-Independent Chemical Shifts(NICS) and get the NICS value of the centric point in ring. The NICS value elucidated successfully the relative stability of compounds, such as 3-acetyl-1H-pyridine-2,4-dione, 2-acetyl-pyran-2,4-dione, 2-acetyl- cyclopent-4-ene-1,3-dione and 2-acetyl-pyrrole-2,4-dione. We also found that the aromaticity of ring plays a crucial role in the relative stability of the isomers, and the influences of the polarity of solvent on tautomerizm could be ignored relatively.In the second part, the active tautomer of the HPPD inhibitor, 2-[2-nitro-4-(triflouromethyl)-benzoyl]-1,3-cyclohexanedione (NTBC) was studied bythe quantitative structure-activity relationship. Based on the fact that the stable tautomer of NTBC by calculation is different from that from X-ray experiment, the quantitative structure-activity relationship (Comparative Molecular Field Analysis, CoMFA and Comparative Molecular Similarity Index, CoMSIA) were studied on the five possible active tautomers in order to conjecture the structure of NTBC binding with HPPD. It was found that the tautomer generating the best model of CoMFA is coincident with that speculated from the dynamic experiment, which offer theoretical foundation for researching the binding pattern. It is the first time that the traditional structure-activity relationship was applied to predict the active structure of ligand successfully.Additionally, the quantum chemical study on the isomeriaation mechanism of the enol ester of 2-acyl-l,3-cyclohexanedione was performed, which was discovered by Yang when he synthesized the derivate of 2-acyl-l,3-cyclohexanedione. The two possible reaction mechanism proposed by Yang and us were calculated at the level of B3LYP/6-31G*, and the influences of solvent effect and catalytic effect of triethylamine on energy barriers of both mechanisms were examined. The results revealed that the mechanism proposed by us is energetically favorable.Finally, a series of model compounds were designed based on the coenzyme pyrroloquinoline quinone PQQ in order to reveal the relationship between the structure of diketone compound and their activity. The nucleophilic additions of ammonia with a series of PQQ model as well as their analogues were investigated at the B3LYP/D95(d,p) level of theory. It is demonstrated that: for the monocarbonyl system, the electrophilicity of the carbonyl carbon affects a lot the reactive energy barrier; for the biscarbonyl system, the hydrogen bond, which is formed in transition state between the hydrogen of the nuclephilic reagent amine and the carbonyl oxygen in ortho-position is crucial for reaction activation energy; Although condensed aromatics has little effect on reactive barrier, the reaction activation energy can be significantly reduced due to the hydrogen bond between H of amine and Ni, giventhere is one nitrogen atom in the 1-position. A good linear correlation has been found quantitatively between the reaction activation energy and the angle (OCN) between the attacked carbonyl and the H of amine, which imply that the stabilizing effect of intramolecular hydrogen bond is the most important factor on the energy barriers for the nucleophilic additions of ammonia with carbonyl compound. All conclusions gained provide reliable theoretical basis for further designing high active quinone catalyst.