Aminolysis of an N-diazeniumdiolated amidine as an approach to diazeniumdiolated ammonia.
Recent theoretical studies have suggested that the parent diazeniumdiolate ion, H2N-N(O)═NO(-) ("diazeniumdiolated ammonia"), might be stable enough to be isolated and that it could potentially serve as a uniquely advantageous prodrug form of bioactive nitroxyl (HNO). Here, we report on an attempt to isolate its O(2)-benzylated derivative by aminolysis of the C═N bond in PhC(NH2)═N-N(O)═NOBn. The reaction proved remarkably sluggish in comparison to aminolysis of unsubstituted benzamidine, and the desired product could not be isolated, apparently because of base sensitivity of the NH2 group. Consistent with this interpretation, O-benzylhydroxylamine and N2O were recovered from the reaction mixture in high yields, along with N,N'-dibutylbenzamidine. Theoretical calculations rationalize the observed slow aminolysis by demonstrating that the diazeniumdiolate group greatly suppresses the electrophilicity of the adjacent C═N carbon center, rendering attack at that position endothermic. The data provide significant insights into the challenges inherent to the pursuit of diazeniumdiolated ammonia.
Drug Design Section, Chemical Biology Laboratory, and ‡Basic Science Program and §Advanced Biomedical Computing Center, Information Systems Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
Debanjan
D
Biswas
Joseph A
JA
Hrabie
Joseph E
JE
Saavedra
Zhao
Z
Cao
Larry K
LK
Keefer
Joseph
J
Ivanic
Ryan J
RJ
Holland
D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry; D000641:Ammonia / Q000737:chemistry*; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D001550:Benzamidines / Q000737:chemistry*; D009589:Nitrogen Oxides / Q000737:chemistry*
D000578:Amidines; D001391:Azo Compounds; D001550:Benzamidines; D009589:Nitrogen Oxides; C452539:diazeniumdiolate; D000641:Ammonia; C039900:nitroxyl; C032157:benzamidine