Quantum Chemical Study Of The Hydrolysis Reaction Mechanism Of Cocaine And Its Family Of Derivatives

Nowadays, the worldwide drug abuse has become one of the most serious problems, and posed an enormous threat to the global peace, stability and the safety of humanity. The abuse of drug seriously affects humanity's health in mind and body, moreover, brings the severe public sanitation problems. It has been a global problem, therefore, the improvement of treatment, the search of vaccine antibody and the consummation of antidote theory are stared in face! Although potential dangers are existing in considerable aspects if vaccine and antidote are directly synthesized with narcotics, it is possible to explore the additive principle of narcotics by the method of quantum chemistry, with the development of computer science and technology of molecular simulation. However, the reactive principle of the narcotics such as morphine, cocaine in human's body is unclear and disputed.Based on this, deep and systemic research has been done theoretically on the active principle of cocaine in this article. At the same time, the research provides important theoretical evidence for the further study on the hydrolysable principle of cocaine in human's body, for the sake of designing the more active one-celled clone antibody which can catalyze the hydrolyzation of cocaine.According to the above situation, this paper passes B3LYP method of DFT, have carried on the whole parameter to optimize (not add limiting to the reactant, product, intermediated complex of different possibility and transition state symmetrically ) on 6-31G* level, have carried on vibration frequency analysis to some of all staying the potential energy on the same theoretical level.The following works have been done by us based on the above research background. 1. As the first step in the understanding of the hydrolysis reaction of cocaine,we studied the hydrolysis reaction of cocaine and three model esters in the methods of ab initio and density functional theory(DFT). In fact, the experimental hydrolysis reactions of cocaine are carried out in the liquid phase. And the presence of the solvent (H₂O) considered as polarizable continuum model are studied in detail in both of the reaction mechanism and the energy barrier.From the above presented discussions, one may draw the following conclusions.1) The reaction coordinate calculations indicate that both the benzoyl-ester hydrolysis and the methyl-ester hydrolysis occur through a two-step process known for the majority of alkyl esters, i.e., the formation of a tetrahedral intermediate by the attack of hydroxide oxygen at the carbonyl carbon (first step) followed by the decomposition of the tetrahedral intermediate to products (second step).2) The solvent effects substantially lowers total energies of all structures but disfavors the reaction energy barriers.3) the first step of the hydrolysis in aqueous solution should be rate-determining for both the cocaine benzoyl-ester and methyl-ester groups.4) We have examined two competing pathways for the second step of cocaine hydrolysis: one associated with the direct proton transfer from the hydroxide/hydroxyl oxygen to the ester oxygen, and the other associated with a water-assisted proton transfer.2. We adapt the way by changing the hydrolysable groups to discuss the influence of the structure of cocaine to the hydrolysable principle, and choose a series of cocaine homologues to calculate. The conclusions can be summarized as following.1) If substitutional groups are H, OH, the hydrogen bond is easily formed with water, and the hydrolyzation of cocaine homologues will be restrained.2) If substitutional groups are acceptor groups, the hydrolyzation of cocaine homologues will be accelerated.3) If substitutional groups are huge groups, the hydrolyzation of cocaine homologues will be. accelerated4) If substitutional groups are huge and acceptor groups, it is difficult to estimate the influence of the hydrolyzation.