An experimental and theoretical study of reaction mechanisms between nitriles and hydroxylamine

Abstract

The industrially relevant reaction between nitriles and hydroxylamine yielding amidoximes was studied in different molecular solvents and in ionic liquids. In industry, this procedure is carried out on the ton scale in alcohol solutions and the above transformation produces a significant amount of unexpected amide by-product, depending on the nature of the nitrile, which can cause further analytical and purification issues. Although there were earlier attempts to propose mechanisms for this transformation, the real reaction pathway is still under discussion. A new detailed reaction mechanistic explanation, based on theoretical and experimental proof, is given to augment the former mechanisms, which allowed us to find a more efficient, side-product free procedure. Interpreting the theoretical results obtained, it was shown that the application of specific imidazolium, phosphonium and quaternary ammonium based ionic liquids could decrease simultaneously the reaction time while eliminating the amide side-product, leading to the targeted product selectively. This robust and economic procedure now affords a fast, selective amide free synthesis of amidoximes.

4-(5-Benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-2-nitrobenzamide

“…Likewise, the enthalpy difference between the two transition states, TS-1-oxime and TS-2-amide varies with the solvent with TS-1-oxime > TS-2-amide in a protic solvent like ethanol, but inverted to TS-2-amide > TS-1-oxime with an ionic solvent. Therefore, the reaction conditions favoring a more stable TS-2-amide might then explain the byproduct formation of the amide [24,25]. Vörös et al reported a theoretical and experimental analysis to describe the byproduct formation (not as the main product) of the amide [24,25].…”

New oxadiazol‐5‐ones derivatives and their performance as angiotensin‐converting enzyme (ACE) inhibitors

“…In this process, the unshared electrons of the nitrogen atom in hydroxylamine attack the carbon in the nitriles. In a proton-rich environment (protic medium), the electronic charge on the carbon atom of the nitriles decreases, making it easier for the unshared electrons of hydroxylamine to attack [14].…”

Functionalized d- and l-Arabino-Pyrrolidines as Potent and Selective Glycosidase Inhibitors

“…The formation of amides in amide oxime synthesis in the presence of Et 3 N has been encountered by others and presumably originates from the primary attack on the nitrile group by the hydroxylamine oxygen. 28,29 The isolated quantities of both amide oxime enantiomers, viz. D-6 and L-6, were sufficient for biological testing.…”