Theoretical Studies On Syntheses Reaction Mechanism Of Two Pharmaceutical Intermediates

The quinolinone skeleton is an important structural moiety which has obvious biological activity and widely present in a variety of alkaloids and pharmacological effects of drugs with different molecular structure. In recent years, the important application value of quinolinone special structure has attracted much research interest in chemists. The growing importance of these compounds has led to the development of new methods for their synthesis. Therefore, in this paper, on the base of the experiments, we study the mechanism of some synthesis reactions by the theory of quantum chemistry method. We calculate the structure characterization of intermediates and transition states and the energy change, getting the reaction kinetics and thermodynamics data to prove the authenticity and accuracy of the micro-reaction mechanism. The research provides a powerful theoretical basis for the development of new and effective synthetic approach in quiolinone skeleton. The structure of this paper is organized as follows:In the first chapter, we will introduce some basis theories and calculation method. The second chapter, which is the main work, is the theoretical study on mechanism of one-pot reaction to form the 3(4H)-quinolinone complex. We investigate the reaction progress by density functional theory, optimize the geometric configuration of the reactants, intermediates, transition states and products, and confirm each intermediates and transition state structure through energy vibration analysis. The results show that the reaction have four possible channels among which the IA pathway that Re→TS1→IM1→TS2→IM2→TS3→IM3→TS4→IM5→TS7→IM9→TS13→IM10→TS14→P3 has the lowest activation energy, is the main access. And then the intrinsic reaction coordinate (IRC) method is performed to search the reaction path. The main theoretical prediction is consistent with the results of the experiment. In addition, atoms in molecules (AIM) theories are used to discuss the bond characteristic of these substances and interaction of orbit. At last, in order to insure that the research results close to the actual system, we also calculate the solvent effects of the reaction by SCRF (PCM) method. The results show that during the reaction the energy of each substance is lower than the gas phase. The solvent effects enhance the energy barrier to some extent. The main theoretical prediction is consistent with the results of the experiment.In practice, the molecules containing quinolinone skeleton, and other similar aromatic ethers, aromatic amines and other fragments have an important position in dye, medicine, daily chemicals, as well as the preparation of polymers area. Therefore, how to find a green simple and convenient method to construct the C-X (X = C, N, O) structure of the important molecular skeleton, has always been the focus of the chemists'concern areas. In the relevant areas they have already achieved some results in which the area of transition metal catalyzed reaction is an important research direction. Furthermore, copper is such an economic and low toxicity of the metal that it has a natural advantage relative to palladium, nickel and other toxic metals.In the third chapter, we select one of the experiment to study in the third chapter: The reaction mechanism of CuI-catalysed formation of ethyl 2-phenylacetoacetate by Becker's three-parameter nonlocal exchange functional and the Lee, Yang, and Parr nonlocal correlation functional (B3LYP).The geometries of the reactants, intermediates, transition states, and products have been optimized and verified by means of vibration frequency calculations. Arylation of ethyl acetoacetate has been investigated by density functional theory using the According to our assumption; this reaction can be divided into two stages. The rate-determining step is found to be the 3→4-TS procedure, which is the first procedure of stage 1. The low energy barrier of 39.85 kcal/mol indicates that this reaction is able to carry out, which is in accordance with the experimental facts. For comparison, we have investigated the reaction mechanism of the same chemical reaction without CuI catalyst, whose energy barrier of rate-determining step is 212.76 kcal/mol higher than that with CuI catalyst. This fact suggests that CuI catalyst accelerates the reaction by remarkably lowering the energy barrier. The solvation effects on the barriers of the reaction are important. But the energetic order in DMSO solvent seems to be almost the same as that in gas-phase, which indicates that our conclusion achieved in gas-phase is believable. Our findings reveal the microscopic catalytic mechanism of CuI and are in agreement with the experiment facts.