"Stability of the S-N Bond in S-Nitrosothiols: Computational and Experi" by Rustam Sabitov

Date of Award

Fall 2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Adam Fiedler

Second Advisor

Dmitri 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).

Available for download on Wednesday, January 28, 2026

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