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.

Analysis of the HNO and NO donating properties of alicyclic amine diazeniumdiolates

“…Secondary amine-based diazeniumdiolates generate NO upon spontaneous decomposition, with reliable half-lives of decomposition ranging from 2 s to 20 h, depending on the amine backbone [36–38]. Importantly, diazeniumdiolates can be readily O 2 -derivatized [39–42], which facilitates purification and increases stability and decomposition half-life, among other effects. Moreover, derivatization allows conversion of diazeniumdiolates to prodrugs that can be bioactivated, thus providing a route to rational design for targeted delivery [43].…”

“…Very recently, the unstable methylamine diazeniumdiolate was characterized and was trapped as the more stable O 2 -benzyl derivative [42]. Under physiological conditions, IPA/NO has a short half-life of 6.7 min [46] and generates HNO via a tautomerization pathway (Scheme 3) [46–48].…”

Decoding Nitric Oxide Release Rates of Amine-Based Diazeniumdiolates

“…Previous computational studies have found that amine-based NONOates should be able to exist in both Z and E forms; 13−16 however, for unclear reasons, only the Z form has been directly synthesized. While primary amine NONOates were theoretically predicted, 15 and later experimentally confirmed, 15,17 to have possible Z ⇌ E interconversion routes via amine deprotonation, no such low energy pathway is possible for secondary amine analogues; therefore, only Z isomers are considered here. Houk and co-workers have shown through computational studies 14,16 experimentally 18 that NO release is initiated via amine protonation.…”

“…Previous computational studies have found that amine-based NONOates should be able to exist in both Z and E forms; − however, for unclear reasons, only the Z form has been directly synthesized. While primary amine NONOates were theoretically predicted, and later experimentally confirmed, , to have possible Z ⇌ E interconversion routes via amine deprotonation, no such low energy pathway is possible for secondary amine analogues; therefore, only Z isomers are considered here. Houk and co-workers have shown through computational studies , and Davies et al have confirmed experimentally that NO release is initiated via amine protonation.…”