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.
Contribution from the Basic Research Program, SAIC Frederick, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Joseph E
JE
Saavedra
D Scott
DS
Bohle
Kamilah N
KN
Smith
Clifford
C
George
Jeffrey R
JR
Deschamps
Damon
D
Parrish
Joseph
J
Ivanic
Yan-Ni
YN
Wang
Michael L
ML
Citro
Larry K
LK
Keefer
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