title: O2-functionalized methylamine diazeniumdiolates: evidence for E ⇄ Z equilibration in an acyclic system.
abstract: Diazeniumdiolates that have the structure RHN-N(O)═NOR' are of interest as prodrug (caged) forms of the bioeffectors nitric oxide (NO) and nitroxyl (HNO). Previous work has focused on examples possessing α-branched R groups, with isopropylamine (IPA)/NO (R = isopropyl) being the smallest examined to date. To probe the effect of minimizing the alkyl-group size on the chemistry of IPA/NO, we prepared the corresponding methylamine derivative as a sodium salt that was highly unstable but could be trapped in very low overall yield as the stable O(2)-benzyl derivative. To prepare enough for efficient characterization, we devised an alternate synthesis involving a novel N-dealkylation route. CH(3)HN-N(O)═NOBn, synthesized in high yield and crystallized as the Z isomer as determined by X-ray crystallography, was observed to exist as a 11:1 mixture of two isomeric forms in dynamic equilibrium in solution. Similar results were seen for the O(2)-ethyl derivative, whose two equilibrium constituents were partially separated by HPLC to reveal essentially identical UV and mass spectra, indicating them to be Z and E isomers of CH(3)HN-N(O)═NOEt. The results could lead the way to a fuller understanding of the chemistry of the acyclic (E)-diazeniumdiolates.
authors.affiliation: Drug Design Section, Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. biswasd@mail.nih.gov
authors.forename: Debanjan
authors.initials: D
authors.lastname: Biswas
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Holland
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Zhao
authors.initials: Z
authors.lastname: Cao
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
mesh_terms: D000478:Alkylation; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry*
chemical_list: D001372:Aza Compounds; D008744:Methylamines; C518951:methylamine diazeniumdiolate; D009569:Nitric Oxide