Theoretical Studies On Nucleophilicity Parameters For π-Nucleophiles And The Mechanism Of Native Chemical Ligation

The development of quantum chemisty and theoretical methods has made it possible to provide in-depth insight into the nature of organic chemisty through computation. This dissertation reports our application of the computational organic chemisty in predicting the nucleophilicity N parameters of variousπ-nucleophiles and investigating the detailed mechanism of native chemical ligation.In Chapter 1, the background of computational organic chemistry and several computational methods including molecular mechanics, Hartree- Fock method, post Hartree-Fock methods and density functional theory methods were briefly introduced.In Chapter 2, we developed an ab initio protocol to predict the nucleophilicity N parameters of variousπ-nucleophiles in CH2Cl2 through transition state calculations. The optimized theoretical model (i.e. BH&HLYP/6-311++G(3df,2p)//B3LYP/ 6-311+G(d,p)/PCM/UAHF) could predict the N values of structurally unrelatedπ-nucleophiles within a precision of ca. 1.14 unit and therefore, may find applications for the prediction of nucleophilicity of compounds that are not readily amenable to experimental characterization. The success of predicting N parameters from the first principles also allowed us to analyze in depth the electrostatic, steric, and solvation energies involved in the electrophile-nucleophile reactions. It was found that solvation did not play an important role for the validity of Mayr's equation. On the other hand, the correlations of the E, N, and logk values with the energies of the frontier molecular orbitals indicated that the electrostatic/charge transfer interactions played vital roles in Mayr's equation. Surprising correlations were also observed between the electrophile-nucleophile C-C distances in the transition state and the activation energy barriers and the E and N parameters, indicating the importance of the steric interactions in Mayr's equation. A method was then proposed to separate the attraction and repulsion energies in the nucleophile/electrophile interaction. It was found that the attraction energy correlated to (N + E), whereas the repulsion energy correlated to the s parameter.In Chapter 3, a systematic theoretical study was carried out to understand the fully detailed mechanism of native chemical ligation. It is found that for the conventional native chemical ligation reaction between a peptide-thioalkyl ester and a cysteine in combination with added aryl thiol as catalyst, both the thiol-thioester exchange step and the transthioesterification step proceed by an anionic concerted SN2 displacement mechanism whereas the intramolecular rearrangement proceeds by an addition-elimination mechanism, and the rate-limiting step is the thiol-thioester exchange step. The theoretical method was then extended to study the detailed mechanism of the auxiliary-mediated peptide ligation between a peptide-thiophenyl ester and an N-2-mercaptobenzyl peptide in which both the thiol-thioester exchange step and intramolecular acyl transfer step proced by a concerted SN2 type displacement mechanism. The energy barrier of the thiol-thioester exchange step depends on the side chain steric hindrance of the C-terminal amino acids while that of the acyl transfer step depends on the side chain steric hindrance of the N-terminal amino acid.These studies can not only reproduce the experimental conclusions bus also afford many information which couldn't be obtained by experiment. The research results in this dissertation are believed to provide valuable and fundamental information to synthetic organic chemistry and bioorganic chemisty.