Oxidation of Heteroatoms N and S

Hydroxylamines play a significant role in modern industrial chemistry. Their most important chemical properties include differential reactivity of the N and O termini, changes in reactivity with pH and solubility in both aqueous and organic solvents. Hence the study of reactions of hydroxylamine derivatives, especially their oxidation to nitroso compounds, constitutes an important area of investigation. 

The oxidation of aromatic hydroxylamines has been widely used in the preparation of nitrosobenzenes. Among the methods described in the literature for this transformation, the most common procedure involves heterogeneous oxidation using iron(III) chloride [140]. This oxidation is normally slow, which can lead to the formation of the corresponding azoxy derivatives through coupling of the formed nitroso compound with the unreacted hydroxylamine. In addition, low yields are sometimes obtained due to the partial instability of the starting hydroxylamine and/ or nitroso product. Illustrative examples of this transformation are shown in Table 3.2 [141]. 

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Oxidation of Heteroatoms (N and S) 117 Table 3.9 Fe(acac)3-Schiff base ligand-catalyzed asymmetric oxidations. 

Due to the electron-withdrawing nature of the attached heteroatoms, the oxidized C, N, and S atoms prove to be quite amenable to nucleophilic attacks in which electrons are added to the central atom. This is an important strategy employed by microorganisms for beginning the degradation of such compounds. 

Bis(trifluoroacetoxy)iodo]benzene (14, BTIB) can be utilized in hexafluoro-2-propanol for the installation of nucleophiles at the ortho-position of para-sub-stituted alkoxyarenes [59-63]. Such reactions have been employed for the construction of carbon-carbon and carbon-heteroatom (N,0,S) bonds, trimethylsi-lyl compounds serving as useful progenitors of the heteroatom nucleophiles (Scheme 20). Oxidative substitutions of this type appear to proceed through arene radical-cations, generated by single electron-transfer within BTIB/sub-strate charge-transfer complexes. 

Because C-H bonds are usually less reactive towards dioxirane oxidation than heteroatoms and C-C multiple bonds, it is instructive to give a few general guidelines on the compatibility of functional groups within the substrate to be submitted to oxidative C-H insertion Substances with low-valent heteroatoms (N, P, S, Se, I, etc.), C-C multiple bonds, and C=X groups (where X is a N or S heteroatom) are normally not suitable for C-H insertions, because these functionalities react preferably. Even heteroarenes are more susceptible to dioxirane oxidation than C-H bonds, whereas electron-rich and polycyclic arenes are only moderately tolerant, but electron-poor arenes usually resist oxidation by dioxiranes. N-oxides and N-oxyl radicals are not compatible because they catalyze the decomposition of the dioxirane. Oxygen insertion into Si-H bonds by dioxirane is more facile than into C-H bonds and, therefore, silanes are not compatible. Substance classes normally resistant towards dioxirane oxidation include the carboxylic acids and their derivatives (anhydrides, esters, amides, and nitriles), sulfonic acids and their de-... 

Methionine (Met) is one of the sensitive sulphur-containing amino-acids toward one-electron oxidation. However its ease of oxidation is also modulated by the structure. The one-electron oxidation of Met in peptides yields sulfide methionine radical cations (MetS +) which convert into intermediates that obtain catalytic support from neighbouring groups containing electron rich heteroatoms (S, N, O) and thus stabilize electron deficient sulphur centres in S.-.S, S.-.N, and S.-.O-three-electron bonded complexes (Fig. 5) [11]. 

In all these reactions, peroxidase behaves as monooxygenase. Such monooxygenase-type reactions are classified [77] in 1) heteroatom (N or S) oxidation, 2) epoxidation and 3) hydroxylation. A representative reaction of N-oxidation is the oxidation of morphine (VIII Ri = R2 = H), codeine (VIII Ri = CH3 R2 = H) and thebaine (VIII Ri = R2 = CH3) to their corresponding N-oxides (IX) (Scheme V) ... 

By weak bonding surface complexation of heteroatom (X = 0, S, or N)-containing substrates, metal oxides (such as Nb20s and Ti02) could... 

Heteroatom (O and N) attachment to the C8-site of dG to form 8-oxo-dG and C8-arylamine adducts lowers the oxidation potential relative to dG. The oxidation potential of 8-oxo-dG is 0.74 V versus NHE. Consequently, 8-oxo-dG can act as a deep radical cation trap within duplex DNA. Depending on the DNA sequence, an 8-oxo-dG lesion will be the preferential site of further oxidation and will protect isolated Gs and GG steps from oxidation the oxidation of 8-oxo-dG by G(—H) occurs with a rate of 4.6 x 10 /M/s. Thus, there is speculation that GC-rich domains outside the coding regions of genes serve to protect the genome from mutagenesis by oxidation. ... 

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. 

The dioxirane oxidation of the C=S and N=S double bonds usually leads to the corresponding 5-oxides. In the latter case, A-oxidation may compete with 5-oxidation , and the experimental results indicate that the chemoselectivity depends on the electron density of these heteroatoms . 

Carbon atoms are classified depending on their hybridization and whether their neighbors are carbon atoms or heteroatoms. Halogen atoms are classified by the hybridization and oxidation state of the C atom to which they are attached. O, S, Se, N, and P are classified in different ways. The model uses 120 different atom-type descriptions and has been developed with a training set of 893 compounds. Observed versus calculated log Kow showed a correlation coefficient of 0.926 and a standard deviation of 0.496. This method has been implemented in the Toolkit. Applications are shown in Figures 13.4.5 and 13.4.6 for the same compounds used to illustrate the Broto et al. method (Figs. 13.4.2 and 13.4.3). 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

The first stage (addition-elimination) is well known with CN and a variety of N-, O- and S-nucleo-philes.7-72-75 The detachment of the product arene from the Fe is more difficult. The conversions in equation (22) demonstrate the stability of the arene-Fe bond toward oxidation, as a side chain methyl is converted to a carboxylic acid, and suggest the generality of heteroatom substitution under mild conditions.76... 

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