Electrophilic oxidation

Pyrroles and furans are particularly easily oxidized. The mechanism of primary attack can be electrophilic, radical or cyclic transition state, and the assignment of individual reactions to these classes is sometimes arbitrary. 

An example of the synthetic utility of the oxidative cleavage of the pyrrole C-2 to C-3 bond is the ring expansion of bicyclic pyrroles (127) to lactams (128) (83S390). 

Bromine or electrolytic oxidation of furan in alcoholic solution gives the corresponding 

5- dialkoxy-2,5-dihydrofuran (129, R=alkyl). Lead tetraacetate in acetic acid oxidation yields 

Oxidants and electrophilic reagents attack pyrroles and furans at positions 2 and 5 in the case of indoles the common point of attack is position 3. Thus, autoxidation of indoles (e.g. 130) gives 3-hydroperoxy-3//-indoles (e.g. 131). Lead tetraacetate similarly reacts at the 3-position to give a 3-acetoxy-3//-indole. Ozone and other oxidants have been used to cleave the 2,3-bond in indoles (132 — 133) (81BCJ2369). 

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The conversion of an alkene to an oxirane by an electrophilic oxidant (Scheme 72) is the commonest route to oxiranes (81H(15)517). The usual laboratory reagent is a peroxy acid... 

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.)... 

Trifluoroacetates of silver, mercury(II), thallium(lll), lead(IV), and lodme(III) are synthetically valuable reagents that combine the properties of strong electrophiles, oxidizers, and Lewis acids Furthermore, trifluoroacetate anions are stable to oxidation, are weak nucleophiles, and usually do not cause any contamination of the reaction mixture... 

Frontier Orbitals and Chemical Reactivity. Chemical reactions typically involve movement of electrons from an electron donor (base, nucleophile, reducing agent) to an electron acceptor (acid, electrophile, oxidizing agent). This electron movement between molecules can also be thought of as electron movement between molecular orbitals, and the properties of these electron donor and electron acceptor orbitals provide considerable insight into chemical reactivity. 

Carboranes as anew class of weakly coordinating anions for strong electrophiles, oxidants, and superacids 98ACR133. 

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. 

In contrast to thiirane oxides, the electrophilic oxidation of thiirene oxides to thiirene dioxides is feasible, probably because both the starting material and the end product can survive the reaction conditions (equation 21). 

Displacement Mechanisms. In these reactions the organic substrate uses its electrons to cause displacement on an electrophilic oxidizing agent. One example is the addition of bromine to an alkene (15-37). 

Phomactin A is the most challenging family member architecturally. The fragments that are most challenging are highlighted in Fig. 8.4. In Box-A, the highly sensitive hydrated furan is prone to dehydration under acidic or basic conditions, and any total synthesis almost certainly must save introduction of this fragment until the end game. Box-B relates to the strained and somewhat twisted electron-rich double bond. This trisubstituted olefin is extremely reactive toward electrophilic oxidants. 

The hydroxylation of C-H bonds by radicals, in contrast to the case of electrophilic oxidants, leads to alcohols without retention of stereochemical configuration. H202, activated by strong acids (superacids (277), HF-BF3 (272), A1C13 (213), and CF3COOH (214)) have been used for the hydroxylation of aromatic compounds. These acid-catalyzed hydroxylations cannot be applied for aliphatic reactants because the hydroxylated products are more reactive than the starting compounds and, hence, they are oxidized further. 

Fig. 9. Electrophilic oxidation of the porphyrin ring by the Fe "-OOH complex formed in the catal3itic turnover of heme oxygenase. The heme group is shown in a truncated form.

In addition to simple electron transfers in which no chemical bond is either broken or formed, numerous organic reactions, previously formulated by movements of electron pairs, are now understood as processes in which an initial electron transfer from a nucleophile (reductant) to an electrophile (oxidant) produces a radical ion pair, which leads to the final products via the follow-up steps involving cleavage and formation of chemical bonds [11-23], The follow-up steps are usually sufficiendy rapid to render the initial electron transfer the rate-determining step in an overall irreversible transformation [24], In such a case, the overall reactivity is determined by the initial electron-transfer step, which can also be well designed based on the redox potentials and the reorganization energies of a nucleophile (reductant) and an electrophile (oxidant). 

The oxidation of sulfides to sulfoxides (1 eq. of oxidant) and sulfones (2 eq. of oxidant) is possible in the absence of a catalyst by employing the perhydrate prepared from hexafluoroacetone or 2-hydroperoxy-l,l,l-trifluoropropan-2-ol as reported by Ganeshpure and Adam (Scheme 99 f°. The reaction is highly chemoselective and sulfoxidation occurs in the presence of double bonds and amine functions, which were not oxidized. With one equivalent of the a-hydroxyhydroperoxide, diphenyl sulfide was selectively transformed to the sulfoxide in quantitative yield and with two equivalents of oxidant the corresponding sulfone was quantitatively obtained. 2-Hydroperoxy-l,l,l-fluoropropan-2-ol as an electrophilic oxidant oxidizes thianthrene-5-oxide almost exclusively to the corresponding cw-disulfoxide, although low conversions were observed (15%) (Scheme 99). Deprotonation of this oxidant with sodium carbonate in methanol leads to a peroxo anion, which is a nucleophilic oxidant and oxidizes thianthrene-5-oxide preferentially to the sulfone. 

Nitrobenzenesulfonylperoxy intermediate 51 had shown a larger oxidizing ability towards olefins compared with the 4-nitrobenzenesulfonylperoxy intermediate. When 2-nitrobenzenesulfonyl chloride reacts with 02" at low temperature (—20 to —35°C) in CH3CN, the corresponding sulfonylperoxy radical 51 or anion 52 is generated. The radical character of the sulfonylperoxy intermediate 51 was further confirmed by the electrophilic oxidizing nature of a 2-nitrobenzenesulfonyl chloride/KOi mixture. 

In order to confirm the radical character of 51 and to extend its utility, oxidations of ary-lacetic acids to the corresponding ketones, aldehydes or alcohols have been conducted. Competitive decarboxylation reactions of phenylacetic acid and p-substituted phenylacetic acids were carried out. The ratio of the rate constants for the decarboxylation of various substituted phenylacetic acids relative to that of phenylacetic acid was found to decrease on decreasing the electron density at the benzylic carbon. Consequently, compound 51 shows an electrophilic oxidation ability towards arylacetic acids, giving a Hammett p value of —0.408. 

It was reported earher that the oxidation of a sulfoxide to a sulfone involves either an initial nucleophihc attack of the nucleophilic oxidant or an electrophihc attack by an electrophilic oxidant. It is noteworthy that the oxidation of p-tolyl methyl, phenyl methyl and p-chlorophenyl methyl sulfoxides to the sulfones using the sulfonylperoxy intermediate 51 appears to be electrophihc, namely the relative reactivity order was p-tolyl methyl > phenyl methyl > p-chlorophenyl methyl sulfoxide based on competitive oxidations. 

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. 

Second, rich bimolecular chemistry (attack by nucleophiles, electrophiles, oxidants, or reductants) that can be used to create reactive intermediates in solution is not generally available in the context of matrix isolation (exceptions to this rule will be discussed in the proper context below). Usually, reactive intermediates to be studied by matrix isolation must be accessible by means of unimolecular processes (fragmentations, rearrangements, ionization) induced by external sources of energy (light or other forms of radiation, discharges). 

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