Decomposition of amino diazeniumdiolates (NONOates): Molecular mechanisms

Although diazeniumdiolates (X[N(O)NO]−) are extensively used in biochemical, physiological, and pharmacological studies due to their ability to release NO and/or its congeneric nitroxyl, the mechanisms of these processes remain obscure. In this work, we used a combination of spectroscopic, kinetic, and computational techniques to arrive at a quantitatively consistent molecular mechanism for decomposition of amino diazeniumdiolates (amino NONOates: R2N[N(O)NO]−, where R = N(C2H5)2 (1), N(C3H4NH2)2 (2), or N(C2H4NH2)2 (3)). Decomposition of these NONOates is triggered by protonation of their [NN(O)NO]− group with the apparent pKa and decomposition rate constants of 4.6 and 1 s− 1 for 1; 3.5 and 0.083 s− 1 for 2; and 3.8 and 0.0033 s− 1 for 3. Although protonation occurs mainly on the O atoms of the functional group, only the minor R2N(H)N(O)NO tautomer (population ~ 10− 7, for 1) undergoes the NN heterolytic bond cleavage (kd ~ 107 s− 1 for 1) leading to amine and NO. Decompositions of protonated amino NONOates are strongly temperature-dependent; activation enthalpies are 20.4 and 19.4 kcal/mol for 1 and 2, respectively, which includes contributions from both the tautomerization and bond cleavage. The bond cleavage rates exhibit exceptional sensitivity to the nature of R substituents which strongly modulate activation entropy. At pH < 2, decompositions of all three NONOates that have been investigated are subject to additional acid catalysis that occurs through di-protonation of the [NN(O)NO]− group.

Decomposition of amino NONOates is triggered by protonation of their [NN(O)NO]− functional group. Although protonation occurs mainly on the O atoms of this group, only the higher-energy, minor R2N(H)N(O)NO tautomer can undergo the rate-limiting N-N heterolytic bond cleavage leading to amine and NO.Figure optionsDownload as PowerPoint slide