Oxygen electrophilic oxidation

FIGURE S.47 The role of glutathione and metabolic pathways involved In the protection of tissues against Intoxication by electrophiles, oxidants and active oxygen species. (Used with permission.)... 

The usual oxidizing agents transfer oxygen (or halogens and related species with subsequent hydrolysis) stepwise to the sulfur of thioethers Rates of step A compared with those of step B are faster with electrophilic oxidation agents (peroxy acids) inversely, rates of step B compared with those of step A are faster with nucleophilic oxidation agents (peroxy anions)339-341. 

We had two possible routes in which alcohol 72 could be used (Scheme 8.19). Route A would involve rearrangement of tertiary alcohol 72 to enone 76. Deprotonation at C5 and generation of the enolate followed by exposure to an oxaziridine or other oxygen electrophile equivalents might directly afford the hydrated furan C-ring of phomactin A (see 82) via hydroxy enone 81. We had also hoped to make use of a chromium-mediated oxidative rearrangement of tertiary allylic alcohols. Unfortunately, treatment of 72 to PCC produced only unidentified baseline materials, thereby quickly eliminating this route. 

Since dioxiranes are electrophilic oxidants, heteroatom functionalities with lone pair electrons are among the most reactive substrates towards oxidation. Among such nucleophilic heteroatom-type substrates, those that contain a nitrogen, sulfur or phosphorus atom, or a C=X functionality (where X is N or S), have been most extensively employed, mainly in view of the usefulness of the resulting oxidation products. Some less studied heteroatoms include oxygen, selenium, halogen and the metal centers in organometallic compounds. These transformations are summarized in Scheme 10. We shall present the substrate classes separately, since the heteroatom oxidation is quite substrate-dependent. 

These observations have been supported by DFT calculations on this system, indicating that the activation energies of the olefin epoxidation step from either the mono- or the bis(peroxo) complex are identical (A = 16.2 kcal mol-1), supporting the observation that both processes are equally relevant. In addition, the epoxidation step is proposed to take place via a nucleophilic attack of the olefin on a peroxidic oxygen atom, i.e., the peroxo complexes behave as electrophilic oxidants [23-25]. 

Electronic Effects. Singlet oxygen is an electrophilic oxidant that exhibits a clear preference for reactions with nucleophilic substrates. This preference is strikingly evident in a comparison of the rates constants for ene reactions of simple methyl substituted alkenes 2,3-dimethyl-2-butene (A = 2.2 x 107M-1s-1) [19] reacts more than 30 times faster than the tri-substituted alkene 2-methyl-2-butene (k = 7.2 x 105 M-1s-1) [19] and more than 500 times faster than the di-substituted alkene Z-2-butene ( = 4.8 x 104M-1s-1) [19]. The practical implications of these electronic effects are... 

The pH dependence may be due to the reactive periodate species being lOJ, but the mechanism of hydroxylation is uncertain. The exceptions noted above show that enolisation cannot be the sole factor determining whether or not hydroxylation occurs, furthermore some weakly enolised compounds (e.g. malonic acid) are readily oxidised. Bose et suggested a cyclic mechanism, but such a mechanism cannot be extended readily to malonic acid, or, for steric reasons, to 1,3-cyclohexanedione (Sklarz ). Bunton has suggested that hydroxylation may occur by IO4 acting as an electrophilic oxidant transferring oxygen to the substrate, viz. 

Although, as stated above, olefin epoxidation is commonly referred to as an electrophilic oxidation, recent theoretical calculations suggest that the electronic character of the oxygen transfer step needs to be considered to fully understand the mechanism [451]. The electronic character, that is, whether the oxidant acts as an electrophile or a nucleophile is studied by charge decomposition analysis (CDA) [452,453]. This analysis is a quantitative interpretation of the Dewar-Chatt-Dimcanson model and evaluates the relative importance of the orbital interactions between the olefin (donor) and the oxidant (acceptor) and vice versa [451]. For example, dimethyldioxirane (DMD) is described as a chameleon oxidant because in the oxidations of acrolein and acrylonitrile, it acts as a nucleophile [454]. In most cases though, epoxidation with peroxides occurs predominantly by electron donation from the 7t orbital of the olefin into the a orbital of the 0-0 bond in the transition state [455,456] (Fig. 1.10), so the oxidation is justifiably called an electrophilic process. 

Dioxiranes, of which DMD is the simplest member, are powerful electrophilic oxidizing agents, able to transfer oxygen to aromatic rings and double bonds. DMD was identified by Ragauskas [113] and Lee and coworkers [114] as a very effective bleaching agent for chemical pulps. It can be added directly to pulps or prepared in situ from acetone and PMS. 

---