A Theoretical Study On Hydrogen Bond Bridge Assisted Proton Transfer

Proton transfer plays an important role in many chemical reactions and biological processes. It is very helpful to understand the mechanism of chemical reactions and life processes by studying the proton transfer process of the nitrogen-containing heterocyclic compounds which is important pharmaceutical intermediates and has a good biological activity. Hydrogen bonding is the fundamental reason for water molecules to associate. The hydrogen bond plays the role of the "bridge" in the proton transfer, double roles of proton acceptor and donator. Whether it is a single water molecules or clusters of water molecules can generate hydrogen bonds reducing the energy of the system. So, it is important to focus on a detailed study of the role and factors of hydrogen bonding bridge assisted proton transfer which can provide some theoretical guidance for the design and screening of drugs and biological synthetic.This article is divided into two parts, as follows:In the first part, the calculation of water-assisted proton transfer base on the synthesis of pyrano[2,3-d]pyrimidine derivatives by density functional method. There are three competitive ways of proton transfer has been designed to complete the pyrano ring from the intermediate a, which gived by pyrimidine ring reacting in a Michael addition reaction. And study of the hydrogen bonds bridge of one water molecule directly involved in the proton transfer process has been taken into considertion. The three paths, both in anhydrated and mono-hydrated case, have been analysed by thermodynamic and kinetic parameters. The result is that the most favorable reaction path is1. The mono-hydrated transition state has a six-membered ring by two hydrogen bonds, which is considerably less strained of the bond angle tension. In this process, double protons take path in the transition and the activation energy of all decreased dramatically. The two water molecules assist process which contains the eight-numbered ring with three hydrogen bonds which angles near to180°.The less deformation from the linear structure causes the H atom easier to transfer and the activation energy further reducing. In order to explore the quantitative relationship between the number of water molecules and the actibation energy, we further study the tri-hydration and tera-hydrated complexes involved in proton transfer isomerization process which indicate that the activation energy of the reaction system is not always decreasing weith the mumber increase of the water molecules because of the space steric effect by long-range hydrogen bonds chains. Therefore, the most favorable bridge is three hydrogen bonds which formed linear structure by two water moleculars. In addition, the solvation effect of water as the reference found that a purely un-catalyzed mechanism for the reaction in aqueous solution would not be a competitive process with respecting to the water-assisted mechanism.The enol-keto tautomerism of pterin under the seven reaction pathways has been calculated by the B3LYP/6-31G(d,p) methods. One is the isolated proton migration and the others are hydrogen bonds bridge formed between three different mono and dimmer molecules (NH3, H2O, HF) with pterin assisted proton migration. The results show that the enery of enol-keto tautomerism is negative, the activation energy is higher than the reverse reaction, and the frontier molecular orbital energy gap of A is higher than B. All of the keto form is the most stable isomer in both isolated molecules and hydrogen bonding complexes. The hydrogen bond bridge geometry, interaction energy, and natural bond orbital stabiliz-ation energy of pterin hydrogen bond complex determine the strength of the hydrogen bonds. The formation of the hydrogen bond bridge can ease the the angle of transition state, which form a multi-hydrogen bond is nearly plane ring, and increase stabilization energy and enhance the role of hydrogen bonds which reduce the activation energy of proton migration significantly. The study also shows that the activation energy of dimer hydrogen bonding complex is lower than the monomer hydrogen bond complexes. Compare with water and amine molecules, whether mono or dimmer hydrogen bonding complex, HF molecule reduce the active energy more obvious.