An exploratory and mechanistic study of the defluorination of an (aminofluorophenyl)oxazolidinone: SN1(Ar*) vs. SR+N1(Ar*) mechanism

Abstract

The morpholinofluorophenyloxazolidinone 1 (the antibacterial drug linezolid) is found to undergo reductive defluorination upon irradiation in water (Phi 0.33), in some of the products accompanied by the simultaneous oxidative degradation of the morpholine side chain. In the presence of chloride, iodide and pyrrole, the fluorine is substituted by these groups (with pyrrole, in position 2). The defluorination is less efficient in methanol and mainly leads to reduction (Phi 0.053). These data can be accommodated through two different mechanisms, viz. either C-F bond heterolysis to give a phenyl cation [S(N)1(Ar*)], or ionization to give a radical cation [S(R(+)N)1(Ar*)]. Steady-state and time resolved data have been gathered for clarifying this issue. It is found that, indeed, ionization of 1 is efficient and proceeds from the singlet, but leads to no irreversible change. On the contrary, triplet (3)1 (lifetime 0.5 micros in MeOH, <0.1 micros in water) fragments and gives the corresponding triplet phenyl cation. The last intermediate explains well the observed hydrogen abstraction both inter- (from the solvent, when this is reducing) and intramolecularly (from the morpholine group), as well as addition to a charged anion or to a neutral pi nucleophile such as pyrrole. The rationalization is supported by the study of some related molecules. Thus, the only photochemical reaction from the non fluorinated analogue of linezolid (that ionizes just as 1) is an inefficient degradation of the morpholine chain (Phi 0.001), while a simple model such as N-(2-fluorophenyl)morpholine undergoes photosolvolysis in water and is not trapped by pyrrole.

Analytical Determination and Electrochemical Characterization of the Oxazolidinone Antibiotic Linezolid

“…Thus, chloride (from the supporting electrolyte) leads to 8 and a vestige of the coupling appears in product 9 , involving previous partial solvolysis of the fluorine. A related stepwise degradation has been observed with alkylanilines and in particular with drugs containing such a moiety by electrochemical 24 or photochemical oxidation 2, 25–28. It may further be noticed that linezolid is known to degrade oxidatively under biological conditions 29 as well as photochemically, although in the latter case the main process is different, viz.…”

“…The solution, that rapidly changed from colourless to dark‐violet and finally to orange, returned colourless after a few minutes. It may be noted that the development of a colour has been observed also upon photoionization, resulting in two absorptions bands at 320 nm and 530–640 nm 2.…”

“…For this reason, stability studies 2 and fast methods for the determination of these antibiotics are required. Linezolid is usually determined by HPLC with UV‐vis or mass spectrometry as detector 3–5; electrochemical techniques, rapid, economic and sufficiently selective, should be considered as well.…”

Structural characterization of a degradation product of rocuronium using nanoelectrospray‐high resolution mass spectrometry

“…Hydrolytic degradation then leads to the degraded morpholine ring bearing N ‐(2‐hydroxyethylamino) and N ‐formyl groups. Further mechanistic details of photo‐oxidative degradation of linezolid was provided by Fasani et al ., who investigated related molecules . The stepwise oxidation of morpholine ring was explained by deprotonation of the cation, to form an enamine, and subsequent hydrolysis and further oxidation of the side chain.…”

“…Further mechanistic details of photooxidative degradation of linezolid was provided by Fasani et al, who investigated related molecules. [20] The stepwise oxidation of morpholine ring was explained by deprotonation of the cation, to form an enamine, and subsequent hydrolysis and further oxidation of the side chain. A detailed electrochemical investigation of the linezolid oxidation was carried out by Merli et al including LC-MS/MS analysis of the oxidation products.…”