Journal
JOURNAL OF ORGANIC CHEMISTRY
Volume 80, Issue 3, Pages 1338-1348Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jo502330w
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Funding
- National Science Foundation [CHE-1213438]
- Cardioxyl Pharmaceuticals
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1213438] Funding Source: National Science Foundation
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A new and versatile class of HNO donors, the (hydroxylamino)pyrazolone (HAPY) series of HNO donors utilizing pyrazolone (PY) leaving groups, is described. HNO, the smallest N-based aldehyde equivalent, is used as a reagent along with a variety of PY compounds to synthesize the desired HAPY donors in what can be considered an N-selective HNO-aldol reaction in up to quantitative yields. The bimolecular rate constant of HNO with PY in pH 7.4 phosphate buffer at 37 degrees C can reach 8 X 10(5) M-1 s(-1). In 1H NMR experiments, the HAPY compounds generate HNO quantitatively (trapped as a phosphine aza-ylide) with half-lives spanning 3 orders of magnitude (minutes to days) under physiologically relevant conditions. B3LYP/6-31G* calculations confirm the energetically favorable reactions between HNO and the PY enol and enolate, whereas HNO release is expected to occur through the oxyanion (OHN-PY) of each HAPY compound. HNO has been shown to provide functional support to failing hearts.
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