Date of Award
Fall 2015
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Timerghazin, Qadir K.
Second Advisor
Reid, Scott
Third Advisor
Dockendorff, Chris
Abstract
S-nitrosothiols (RSNOs) are biologically important molecules involved in the storage and transport of nitric oxide (NO) and account for much of its signaling activity in living organisms. RSNOs have significant impact on NO signaling through, S-nitrosation, a major post-translational modification of proteins. These unstable thiol derivatives readily undergo homolytic dissociation of the S–N bond to release NO. RSNOs have potential therapeutic applications as NO donors, although the development of novel RSNOs has been slow due to the complex electronic structure of the –SNO group. A specific focus on the impact of the –R group on RSNO properties via substituent effect study, should serve as a reliable means for systematic development of new RSNOs. In this work, electronic structure calculations have been used to investigate substituent effects in RSNOs. A library of substituents was developed for substitution in several RSNO models, with emphasis on aromatic RSNOs (ArSNOs). Para-substituted PhSNOs showed a significant substituent effect despite the lack of conjugation between the –SNO group and substituent due to the non-planar nature of the –SNO group with the aromatic ring. A thorough computational study of PhSNO as the parent ArSNO revealed the primary mode of substituent effect, a novel cascading double conjugation. This conjugation motif involves the long-range delocalization of electron density from the oxygen lone pair to σSN* orbital and then to the phenyl ring π-system, effectively connecting the –SNO group and substituent positions of the aromatic ring. Detailed analysis of vinyl-substituted RSNO (VinSNO) was performed to further understand the fundamental interaction of a π-system with an adjacent –SNO group. The impact of the vinyl π-bond on the adjacent –SNO group of VinSNO again revealed cascading double conjugation as the dominant feature. In general, cascading double conjugation will effectively destabilize the S–N bond in ArSNOs, specifically those RSNOs with a π-system adjacent to the –SNO group. Computational study of PhSNO and VinSNO was also carried out using Lewis acids and external electric fields (EEFs) to explore their effect on the –SNO group as well as the cascading double conjugation. Application of both resulted in substantial modulation of the –SNO group properties. Furthermore, use of Lewis acids or EEF, in tandem with select substituents, is expected to improve the functionality of ArSNOs as NO donors and advance the development of novel RSNOs.