EXAMINATION OF THE N TO PI STAR INTERACTION AND THE PROLINE AMIDE BOND EQUILIBRIUM

Abstract

The focal point of this thesis is the tertiary amide bond that is unique to proline and hydroxyproline among the proteogenic amino acids. The tertiary amide bond has many consequences biologically. Chief among them is the greatly increased population of the cis amide bond compared to the other amino acids. Ronald Raines of the University of Wisconsin has developed a theory whereby the amide bond equilibrium is derived from the pyrrolidine ring pucker and substituents, through their effect on the n → π* interaction. Three studies were devised to probe Raines’ hypothesis. One study was designed to test the relationship between ring pucker and the cis/trans amide bond equilibrium through a deuterium conformational isotope effect. The second study was designed to test the importance of the n → π* interaction by removing the functional group bearing the π* orbital. The third study was designed to test the impact of the n electron character through substituted aroyl amides. In each of these projects, a multifaceted approach was taken using NMR, XRD, and in silico methods. In addition to the findings of these studies, I learned a great deal about how to learn, talk to experts, read, try, and repeat (if not necessarily in that order).