Quinone-sensitized Steady-state Photolysis of Acetophenone Oximes Under Aerobic Conditions: Kinetics and Product Studies†

Abstract

Oxidation of oximes via photosensitized electron transfer (PET) results in the formation of the corresponding ketones as the major product via oxime radical cations and iminoxyl radicals. The influence of electron-releasing and electron-accepting substituents on these reactions was studied. The observed substituent effect strongly supports formation of iminoxyl radicals from the oximes via an electron transfer-proton transfer sequence rather than direct hydrogen atom abstraction. Correlation of the relative conversion of the oximes with Hammett parameters shows that radical effects dominate for the meta-substituted acetophenone oximes (rho(rad)/rho(pol) = 5.4; r2 = 0.93), whereas the para-substituted oximes are influenced almost equally by radical and ionic effects (rho(rad)/rho(pol) = -1.1; r2 = 0.98). From these data sets we conclude that the follow-up reactions proceed through a number of intermediates with both radical and ionic character. This was confirmed by product studies with the use of an isotopically labeled nucleophile. In addition to the major oxidation product (ketone), a chlorine-containing product was often identified as well. Studies on the formation of this product show that the most likely pathway is either via a direct nucleophilic addition in a complex formed between the oxime radical cation and the chloranil radical anion or via a radical substitution (SH2) mechanism. These studies show that with the increasing use of oximes as drugs and pesticides, intake of these chemicals followed by enzymatic oxidation may result in the formation of a variety of reactive intermediates, which may lead to cell and tissue damage.

Assessing and minimizing time-dependent inhibition of cytochrome P450 3A in drug discovery: A case study with melanocortin-4 receptor agonists

“…It is hypothesized that the adduct contained a gemcyanonitroso structure resulting from capture of a reactive oxime derivative by cyanide ion ( Figures 3 and 6). A proposed reaction mechanism involves further oxidation of the oxime to a putative nitroso carbocation which reacts with À CN to form the final product (Park et al 2006) (Figure 6). The oxime would be expected to exist in a tautomeric equilibrium with the corresponding nitroso species, several of which are known to form an metabolite intermediate complex with P450, leading to inactivation of the enzyme (Figure 6).…”

Mechanistic Investigation of the Formation of Isoindole N-Oxides in the Electron Transfer-Mediated Oxidative Cyclization of 2′-Alkynylacetophenone Oximes

“…Oxime-derived compounds have a broad range of applications such as industrial chemicals, − pharmaceuticals, − and antidotes for nerve gas poisoning. − Because oximes and oxime ethers contain two heteroatoms, they are popular reagents for the synthesis of heterocycles, including natural products and pharmaceuticals via intermolecular and intramolecular reactions. − We have previously reported on the use of 2′-arylbenzaldehyde oxime ethers as precursors for the synthesis of phenanthridine derivatives under photoinduced electron transfer (PET) conditions . This work was based on the observation that oxime ether radical cations underwent intermolecular nucleophilic attack at the nitrogen, whereas oximes did not show such reactivity but instead formed the corresponding carbonyl or nitrile via the proposed iminoxyl or iminoyl radicals. , The intermediate oxime radical cations are highly acidic and quickly lose a proton to form an iminoxyl radical, which might be more prone to react with a built-in radical trap. ,, Our initial study on the oxidative cyclization reactions of oximes and oxime ethers showed that built-in aromatic rings behaved as nucleophiles reacting with the nitrogen atom of the oxime ether moiety . Because the oximes did not show such reactivity, it was proposed that aromatic rings do not act as radical traps.…”

“…Given the differences that we observed between the metal-catalyzed cyclization reactions − and the oxidative cyclization reactions of the 2′-arylbenzaldehyde oxime ethers under PET conditions, we set out to investigate the behavior of alkyne groups in a set of ortho -alkynyl benzaldehyde and acetophenone oximes and oxime ethers under PET conditions (see Figure ). Our recent work has shown that radical cation intermediates are easily generated when using oxime ethers and 9,10-dicyanoanthracene (DCA) as the sensitizer or with chloranil (CA) as the sensitizer. ,, However, previously, we have proposed that using CA as a sensitizer in the PET reactions of oximes results in the formation of iminoxyl radicals, presumably because the CA radical anion is a basic species and aids in the deprotonation of the oxime radical cation (as seen by formation of the semiquinone radical under those conditions) . Alternatively, because the DCA radical anion is not a strong base, using DCA as the photosensitizer could allow us to generate the oxime radical cations without facilitating the deprotonation step.…”

O−H Bond Dissociation Enthalpies of Oximes: A Theoretical Assessment and Experimental Implications

“…[32][33][34][35][36][37][38] Furthermore, according to the proposed mechanism for the photooxidation of aldoximes that can yield the corresponding aldehyde and nitrile, the aldehyde/nitrile product ratio is largely determined by the relative stability of the iminoxyl radical as compared with the iminoyl radical. 31,39 Due to these reasons, it is important to acquire a sound knowledge about the O-H BDEs of various types of oximes. Unfortunately, during the past several decades, there have been some heated controversies over the experimental values of oxime O-H BDEs.…”