Repository logo
 

Mechanistic Studies on the Decomposition of Photoactive Nitrosyl Hydride (HNO) Precursors

Files

Thesis(18.39 MB)

Date

2019

Authors

Supervisor

Brasch, Nicola
Blackman, Allan
Simpson, M. Cather

Item type

Thesis

Degree name

Doctor of Philosophy

Journal Title

Journal ISSN

Volume Title

Publisher

Auckland University of Technology

Abstract

Nitroxyl hydride (HNO) is a biologically relevant, highly reactive molecule and is a redox cousin of NO. HNO shows extremely promising pharmacological properties, including treating congestive heart failure. The overarching motivation for this research is to facilitate kinetic and mechanistic studies of HNO with biologically relevant molecules. As HNO rapidly dimerizes in aqueous solution, HNO studies require compounds that release HNO upon demand. However, the release of HNO from thermally decomposing molecules is slow (typically minutes to hours), making kinetic and mechanistic studies challenging. There is increasing interest in the development of photoactive HNO donor molecules because the use of light to activate HNO release enables a high degree of temporal and spatial control. In an effort to meet this need, a Piloty’s acid derivative comprising an HNO-generating trifluoromethanesulfonamidoxy moiety tethered to the (6-hydroxynaphthalene-2-yl)methyl (6,2-HNM) photocage (4) is evaluated in order to establish if it can rapidly and cleanly generate HNO upon light activation. The photodecomposition of 4 was probed under a range of solvent conditions using a combination of characterization techniques, including ¹H NMR spectroscopy, ¹⁹F NMR spectroscopy, high resolution mass spectrometry (HRMS), steady state fluorescence spectroscopy, and time-resolved transient absorption spectroscopy. Photodecomposition of donor 4 occurred via two pathways: via concerted C-O and N-S bond cleavages to release ¹HNO, the 6,2-HNM carbocation, and trifluorosulfinate, CF₃SO₂⁻; or via heterolytic N-O bond cleavage to generate the sulfonamide CF₃SO₂NH₂, and 6-hydroxynaphthalene-2-carbaldehyde. The selectivity between the two pathways is highly responsive to solvent. Donor 4 is shown to decompose to selectively release HNO upon excitation in a solvent mixture of 80:20 v/v MeCN to 5 mM phosphate buffer (pH 7.0). HNO characterization was achieved using two trapping molecules, aquacobalamin and glutathione, and from observation of its dimerization product, N₂O. Evidence for concerted heterolytic C-O and N-S bond cleavages versus elimination of CF₃SO₂NHOH was obtained by ¹⁹F NMR spectroscopy under pH conditions where CF₃SO₂NHOH is stable. ¹H NMR and UV-vis spectroscopic titration experiments showed that donor 4 exists in three protonation states (pKa(NH) = 4.39 ± 0.06 and ₚKₐ(NH) = 9.73 ± 0.01, 25.0 ºC, aqueous solution). Importantly, HNO photorelease occurs from donor 4 under conditions where the naphtholic OH is protonated and the nitrogen atom is deprotonated. Despite exhibiting both photoacidity and photobasicity, release of HNO from donor 4 does not require water and hence does not involve excited state proton transfer(s). Indeed, deprotonation of the photoacidic site of donor 4 decreases pathway selectivity for the generation of HNO following photolysis. The time-resolved spectroscopic studies indicate that HNO release may occur on the picosecond timescale following excitation of donor 4 and occurs via the short-lived ¹NO⁻ species (¹HNO/¹NO⁻ ₚKₐ ~23). Studies were also completed towards determining the rate constant for the reaction between HNO and hydroxycobalamin. A thermally decomposing HNO donor (Piloty’s acid) was used; this HNO donor releases HNO in alkaline conditions. Under alkaline conditions, a pH-dependent mixture of ¹HNO and ³NO⁻ was formed from the decomposition of Piloty’s acid. ³NO⁻ itself is a good reductant, and a reaction of ³NO⁻ and hydroxycobalamin was observed. Furthermore, ³NO⁻ reacts with the product of the reaction between hydroxycobalamin and ¹HNO/³NO⁻ namely nitroxylcobalamin.

Description

Keywords

Nitroxyl, HNO, Photochemistry, Photocage, Time-resolved transient absorption spectroscopy, HNO trapping, Cobalamin, Laser flash photolysis, Nitrosyl hydride, Photolysis, Mechanism

Source

DOI

Publisher's version

Rights statement

Permanent link

https://hdl.handle.net/10292/12522

Collections

Doctoral Theses