Predicting pKa : theory and applications

Abstract

This thesis is concerned with the development of computational procedures for making reliable estimates of general acidities in the gas and condensed phases, and also their application in the study of substituent effects on acids that are important in biology and synthesis. This could provide new insights into the mechanism of enzymatic reactions, as well as improve the control of the (e.g stereochemical) outcomes of certain synthetic reactions. The main focus of this thesis is on methods based on thermodynamic cycles which combine high-level ab initio gas phase energies with solvation free energies from continuum solvent models to yield the solution reaction free energy. Various thermodynamic cycles have been investigated, including the direct/absolute method, the proton exchange method as well as the hybrid cluster-continuum schemes that employ explicit solvent molecules. A thorough assessment of the performance of these cycles in predicting general aqueous acidities has been carried out to help identify a generally applicable approach for chemically accurate pKa prediction. Through this work, a reference-independent cluster-continuum proton exchange scheme has been developed which performed well for small and conformationally rigid acids of various functionalities. Additionally, a class of larger and conformationally flexible polyprotic acids, known as oxicams, has also been studied, and issues related to modeling of these more complex acids are highlighted.

Using the methods developed from this work, the effects of various amide nitrogen substituents on the stability of amide and peptide enolates in the gas and condensed phase were investigated. An unusual distal effect was discovered whereby N-electron-withdrawing substituents and hydrogen bonding to the amide nitrogen were found to significantly increase the acidity of the distal {u03B1}-carbon compared with that proximal to the amide nitrogen. The extent of the effect was such that the {u03B1}-carbon acidities of some N-substituted amides were found to exceed those of typical ketones. The origin of these substituent effects was examined and validated via experimental NMR kinetic measurements, and their relevance to the mechanism of isomerase-catalysed peptide epimerization is also discussed. Additionally, synthetic work has been carried out to demonstrate how these effects might be exploited in synthesis.