Date of Award

12-3-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Adam Fiedler

Second Advisor

Demitri Babikov

Third Advisor

Scott Reid

Fourth Advisor

James Gardinier

Abstract

S-Nitrosothiols (RSNOs) are chemical compounds capable to transport nitric oxide (NO) and show promise in the treatment of cardiovascular diseases. RSNOs occur naturally in-vivo, and others have been synthesized in-vitro as potential drug candidates for NO transport and release. However, RSNOs are inherently unstable due to their weak S–N bond (D0(S-N)=25–30 kcal/mol), so developing a deeper understanding of the factors influencing the RSNOs stability is crucial. In Chapter 2, we investigated the substituent effect on the -SNO group properties. Substituting R– in RSNOs with more electro-donating character can stabilize the –SNO group according to the Natural Resonance Theory (NRT). But modeling the RSNOs is a complex task requiring usage of CCSD(T)/CBS(Q-5) or CCSD(T)-F12a/CBS(T-Q) methods with the inclusion of different corrections (core-valence(∆CV), scalar relativistic(∆SR), spin-spin coupling(∆SO), and high order corrections(∆HO)) to predict properties of RSNOs accurately, specifically r(S–N) and D0(S-N). Here, H-SNO, H3C-SNO, H3Si-SNO were studied using high-level coupled cluster methods, CCSD(T)/CBS(Q-5) and CCSD(T)-F12a,b,c/CBS(T-Q), with various basis sets, cc-pVnZ-F12 and aug-cc-pV(n+d)Z (where n=D, T, Q and 5 (for aug-cc-pV(5+d)Z) with the addition of various corrections to correlation effects (∆CV, ∆SR, ∆SO, ∆HO). It was found that r(S–N) is longer in the cis-H3Si-SNO and cis-H-SNO than in the cis-H3C-SNO. Additionally, D0(S-N) is higher in the cis-H3C-SNO than in the cis-H-SNO and cis-H3Si-SNO. In Chapter 3, experimentally, Ph₃SiSNO and i-Pr₃SiSNO were synthesized and characterized at temperatures below –35 °C. These silicon-containing RSNOs are stable at –45 °C but begin to decompose above –41 °C. Variable-temperature NMR studies determined the plausible rotational energy barrier for cis-trans isomerization of Ph₃SiS¹⁵NO to be approximately 8.86 kcal/mol, which is lower by 3–4 kcal/mol than for carbon-substituted RSNOs. UV-Vis spectroscopy and TD-DFT calculations supported the formation of these compounds. The EPR spectroscopy at 77 K was used to study the relatively stable Ph₃SiS˙ and i-Pr₃SiS˙ radicals. In Chapter 4, DFT and NBO analyses provided insights into the electronic origins of the observed instability of silicon-substituted RSNOs. Hyperconjugative interactions, specifically n(S) → σ*(Si–H), play a crucial role in modulating the properties of the -SNO group. Deletion of these interactions led to a decrease in the S–N bond length (~0.05 Å) and an increase in bond dissociation energy, indicating that the silicon atom enhances interactions n(S) → σ*(Si–H) that weakens the S–N bond strength. A correlation was established between the electronegativity of the substituent and the S–N bond strength; increase in electronegativity decreases the bond strength due to increased hyperconjugative n(S) → σ*(R–X) interactions. In Chapter 5, we are expanding investigation on the crucial influence of non-covalent interaction with σ-hole of Sulfur on stability of S-Nitrosothiols using the high-level ab initio and DFT methods. It was found that π systems can interact with -SNO group via σ-hole of sulfur. Such interaction promotes the partial double bond character in the S-N bond, or promotion of D resonance structure, and simultaneously reduces the ionic character of RS-/NO+ (which destabilizes the -SNO group). Additionally, our calculation predicts that in the protein environment interaction of π-systems with σ-hole of -SNO group tends to profoundly effect on the -SNO group properties (electronic structure and reactivity).

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