“Catch-and-Release” of HNO with Pyrazolones

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 °C can reach 8 × 105 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.