Exploring the Reactivity of N-Heterocyclic Carbene Nitric Oxide Radicals

Abstract

Nitric oxide (NO), a simple free radical, is involved in essential functions such as cardiovascular homeostasis and immune response as a signaling molecule in biological systems. N-Heterocyclic carbenes (NHCs), which are persistent singlet carbenes stabilized by adjacent nitrogen atoms, display noteworthy reactivity with various small molecules and outstanding ability to stabilize reactive species, due to their amphiphilic characters. In 2015, we reported the synthesis and characterization of N-heterocyclic carbene nitric oxide radicals (NHC–NOs) from the reaction between NO gas and NHCs. Furthermore, the application of NHC–NO for controlled NO delivery was showcased using high-intensity focused ultrasound (HIFU) as the triggering stimulus. In chapter Ⅱ, I endeavored to improve the efficiency of NO delivery through theoretical analysis. Enhancing the efficiency of NO release from NHC–NOs necessitates a deliberate and strategic design approach for NHCs. Theoretical calculations enable the anticipation of properties for NHCs and NHC–NOs without synthesizing them. Here, I utilized data-driven tools developed by the Sigman group to establish correlations between molecular descriptors of NHC and free energy difference of the NO release reaction using multivariate linear regression (MLR) analysis. The free energy models for both NHC–NO formation and NO release underscore the significance of the singlet-triplet energy gap of NHC. This study provides valuable insights into the thermodynamics and kinetics of NHC–NOs, offering predictive models to design NHCs tailored for NO release applications. In chapter Ⅲ, I have undertaken a systematic investigation of the electron- and proton-transfer chemistry of [NHC–NO]• compounds. I have accessed a suite of compounds, comprised of [NHC–NO]+, [NHC–NO]−, [NHC–NOH]0, and [NHC– NHOH]+ species. In particular, [NHC–NO]− was isolated as potassium and lithium ion adducts. Most interestingly, a monomeric potassium [NHC–NO]− compound was isolated with the assistance of 18-crown-6, which is the first instance of a monomeric alkali N-oxyl compound to the best of our knowledge. Furthermore, the theoretical analysis was performed to compare NHC nitrosyl derivatives with a metal nitrosyl complex and oxime radicals. These results demonstrate that [NHC–NO]• exhibits redox behavior broadly similar to metal nitrosyl complexes, which opens up more possibilities for utilizing NHCs to build on the known reactivity of metal complexes.