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Chemistry of the diazeniumdiolates. O- versus N-alkylation of the RNH[N(O)NO](-) ion

  1. Author:
    Saavedra, J. E.
    Bohle, D. S.
    Smith, K. N.
    George, C.
    Deschamps, J. R.
    Parrish, D.
    Ivanic, J.
    Wang, Y. N.
    Citro, M. L.
    Keefer, L. K.

  2. Author Address

    SAIC Frederick, Basic Res Program, NCI, Ft Detrick, MD 21702 USA. McGill Univ, Dept Chem, Montreal, PQ H3A 2K6, Canada. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. NCI, SAIC Frederick, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA Keefer, LK, SAIC Frederick, Basic Res Program, NCI, Ft Detrick, MD 21702 USA
    1. Year: 2004
    2. Date: OCT 13
  2. Journal: Journal of the American Chemical Society
    1. 126
    2. 40
    3. Pages: 12880-12887
  4. Type of Article: Article
  1. Abstract:

    Monomethylation of the potentially ambident RNH[N(O)NO](-) ion (R = isopropyl or cyclohexyl) has been shown to occur at the terminal oxygen to yield the novel diazeniumdiolate structural unit, RNHN-(O)=NOMe. The NH bond of the product proved acidic, with a pK(a) of 12.3 in aqueous solution. The ultraviolet spectrum showed a large bathochromic shift on ionization (lambda(max) 244 --> 284 nm, epsilon(max) 6.9 --> 9.8 mM(-1) cm(-1)). Deprotonation led to a pH-dependent line broadening in the H-1 NMR spectrum of iPrNHN(O)=NOMe, suggesting a complex fluxionality possibly involving isomerizations around the N-N bonds. Consistent with this interpretation, evidence for extensive delocalization and associated changes in bond order on ionizing RNHN(O)=NOR' were found in density functional theory calculations using Gaussian 03 with B3LYP/ 6-311 ++G** basis sets. With MeNHN(O)=NOMe as a model, all N-N and N-O bonds lengthened by 0.04-0.07 A as a result of ionization except for the MeN-N linkage, which shortened by 7%. These anions can be N-alkylated to generate (RRNN)-R-1-N-2(O)=NOR3 derivatives that would otherwise be difficult to access synthetically. Additionally, some RNHN(O)=NOR' species may display unique and beneficial pharmacological properties. As one example, an agent with R = isopropyl and R' = beta-D-glucosyl was prepared and shown to generate nitric oxide in the presence of glucosidase at pH 5

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  1. View record in Web of Science®
  2. WOS: 000224357700055

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