Chemistry of the diazeniumdiolates. O- versus N-alkylation of the RNH[N(O)NO](-) ion.
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 (1)H 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 R(1)R(2)NN(O)=NOR(3) 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.
Saavedra
Joseph E
JE
Contribution from the Basic Research Program, SAIC Frederick, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Bohle
D Scott
DS
Smith
Kamilah N
KN
George
Clifford
C
Deschamps
Jeffrey R
JR
Parrish
Damon
D
Ivanic
Joseph
J
Wang
Yan-Ni
YN
Citro
Michael L
ML
Keefer
Larry K
LK
D000478:Alkylation; D000588:Amines / Q000737:chemistry*; D000838:Anions; D001391:Azo Compounds / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D009569:Nitric Oxide / Q000737:chemistry*; D009584:Nitrogen / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet
D000588:Amines; D000838:Anions; D001391:Azo Compounds; C452539:diazeniumdiolate; D009569:Nitric Oxide; D009584:Nitrogen; D010100:Oxygen