Hydroperoxy complexes

Fig. 14. Manifold of reactive species produced from the reaction of a heme group with oxygen and two reducing equivalents. The rate of conversion of A to B limits the lifetime (and therefore reactivity) of the Fe peroxo anion. The rate of formation of the ferryl species C via the Fe -OOH complex B competes with the intramolecular hydroxylation reaction to give hydroxyheme. Reactions of the Fe -hydroperoxy complex B with exogenous electrophilic substrates must compete with conversion of the intermediate to both C and meso-hydroxyheme. The Fe -OOH complex B can also be formed directly with H2O,.

This method of preparation was originally reported by Mimoun and coworkers.74 The intermediate hydroperoxy complex is rarely isolated, especially in the presence of hydrogen peroxide, however if an alkylperoxide is employed, then the ring closure reaction does not take place and alkylperoxo species are formed.75 The triangular metal oxirane species formed is of immense importance for the purpose of oxygen transfer to organic substrates. 

The latter method has the drawback that it can only be applied successfully to a limited number of compounds, such as [(RC02)Pd(00H)2] (R = CF3, CH3)77 and [(CH3C02)Cu2(0H)2(00H)] .78 Alternative synthetic procedures leading to group VIII metal hydroperoxy complexes involve either oxygen insertion into a metal hydride bond79 or protonation of easily accessible metal oxirane complexes with strong acids.80... 

In fact the reaction of H2O2 with Fe3+ leads to the formation of Fe(III)-hydroperoxy complexes Fem(H02)2+ and Feni(0H)(H02)+. At very high concentrations of H2O2, the formation of diperoxo complexes has also been suggested. Kinetic modelling of such a case is complicated and can be found in special literature. 

The limited use of P450-catalyzed reactions in industry stems (at least to some extent) from the high cost of NAD(P)H cofactors. Consequently, several approaches have been developed and snccessfully applied to avoid the use of natural nicotine amide cofactors including chemical, electrochemical, and photochemical reduction of the heme Fe. Another approach aiming to minimize the amount of NAD(P)H required comprises enzymatic cofactor regeneratiou Moreover, several methods were described to directly convert P450s from their resting state into their active ferric hydroperoxy complex form, which enables substrate conversion without the need for cofactors or redox partners. 

Peroxides that directly convert the heme iron of P450s to a ferric hydroperoxy complex by the peroxide shunf (e.g., hydrogen peroxide, cumene peroxide, or tert-butyl oxide) could be useful for oxidation of various substrates. The essential problem in utilizing the peroxide shunf for P450 biocatalysis seems to lie in the time-dependent degradation of the heme and in oxidation of the protein [169, 170]. Methods of directed evolution, tike random and site-specific mutagenesis, were applied to evolve P450s to enhance the efficiency of the peroxide shunt pathway [171]. 

The ff-oxidation of carbonyl compounds may be performed by addition of molecular oxygen to enolate anions and subsequent reduction of the hydroperoxy group, e.g. with triethyl phosphite (E.J. Bailey, 1962 J.N. Gardner, 1968 A,B). If the initially formed a-hydroperoxide possesses another enolizable a-proton, dehydration to the 1,2-dione occurs spontaneously, and further oxidation to complex product mitctures is usually observed. 

Complex formation constants could also be determined directly from UV spectrophotometric measurements. Addition of tert.-butyl hydroperoxide to a solution of nitroxide I in heptane at RT causes a shift of the characteristic absorption band of NO at 460 nm to lower wavelengths (Fig. 9). This displacement allows calculation of a complex equilibrium constant of 5 1 1/Mol. Addition of amine II to the same solution causes reverse shift of theC NO" absorption band. From this one can estimate a complex formation constant for amine II and +00H of 12 5 1/Mol (23 2 1/Mol was obtained for tert.-butyl hydroperoxide and 2,2,6,6-tetramethylpipe-ridine in ref. 64b). Further confirmation for an interaction between hindered amines and hydroperoxides is supplied by NMR measurements. Figure 10a shows part of the +00H spectrum in toluene-dg (concentration 0.2 Mol/1) with the signal for the hydroperoxy proton at 6.7 ppm. Addition of as little as 0.002 Mol/1 of tetra-methylpiperidine to the same solution results in a displacement and marked broadening of the band (Fig. 10b). 

Inhibition and stimulation of LOX activity occurs as a rule by a free radical mechanism. Riendeau et al. [8] showed that hydroperoxide activation of 5-LOX is product-specific and can be stimulated by 5-HPETE and hydrogen peroxide. NADPH, FAD, Fe2+ ions, and Fe3+(EDTA) complex markedly increased the formation of oxidized products while NADH and 5-HETE were inhibitory. Jones et al. [9] also demonstrated that another hydroperoxide 13(5)-hydroperoxy-9,ll( , Z)-octadecadienoic acid (13-HPOD) (formed by the oxidation of linoleic acid by soybean LOX) activated the inactive ferrous form of the enzyme. These authors suggested that 13-HPOD attached to LOX and affected its activation through the formation of a protein radical. Werz et al. [10] showed that reactive oxygen species produced by xanthine oxidase, granulocytes, or mitochondria activated 5-LOX in the Epstein Barr virus-transformed B-lymphocytes. 

Suppression of the Pummerer reaction (Fig. 24) could also be a manifestation of the stabilization of the persulfoxide which prevents its interconversion to the hydro-peroxysulfonium ylide, HPSY (Fig. 25), which is the intermediate that has been suggested to undergo a 1,2-shift of the hydroperoxy group and ultimately produces the SC bond cleavage products.92 However, the situation is probably more complex since the intrazeolite reaction of /1-chlorosulfide, 29 (Fig. 28A), requires 7-hydrogen abstraction. The complexation motif (Fig. 28B) which favors the extended rather than folded M+-PS may also play an important role. A complete understanding of these reactions will require additional studies. 

Fig. 28 A. Intrazeolite photooxygenation of a -chlorosulfide that requires a hydroperoxy sulfonium ylide and B. The formation of an extended cation complexed persulfoxide that can potentially inhibit hydroperoxy sulfonium ylide formation.

A closer examination by ex situ analysis using NMR or gas chromatography illustrates that intrazeolite reaction mixtures can get complex. For example photooxygenation of 1-pentene leads to three major carbonyl products plus a mixture of saturated aldehydes (valeraldehyde, propionaldehyde, butyraldehyde, acetaldehyde)38 (Fig. 33). Ethyl vinyl ketone and 2-pentenal arise from addition of the hydroperoxy radical to the two different ends of the allylic radical (Fig. 33). The ketone, /i-3-penten-2-one, is formed by intrazeolite isomerization of 1-pentene followed by CT mediated photooxygenation of the 2-pentene isomer. Dioxetane cleavage, epoxide rearrangement, or presumably even Floch cleavage130,131 of the allylic hydroperoxides can lead to the mixture of saturated aldehydes. 

The carbanions take up 02 and these take up protons to give hydroperoxides in good yields. But because they are explosive in nature, they are not usually isolated and on reduction with sodium sulphite on trialkyl phosphite give alcohols. Alcohols can also be prepared via hydroperoxy molybdenum complexes and alkyl boranes. These reactions are summarized as follows ... 

Complexation of sodium to the persulfoxide A (Fig. 13B) appears to inhibit intramolecular hydrogen abstraction to form the hydroperoxy sulfonium ylide (B in Fig. 13A) and allows a direct reaction of 12 with the sodium-complexed persulfoxide, (A in Fig. 13B) to compete. Consistent with this suggestion is the observation that the formation of 13CHO that emanates from the hydroperoxy sulfonium ylide by Pummerer rearrangement and subsequent cleavage is completely suppressed during photo-oxidations of thiolane, 13, in NaMBY ... 

The allylic hydroperoxide, 2,3-dimethyl-3-hydroperoxy-l-butene, III, was detected during the oxidation of TME in the presence of [MCl(CO)-(Ph3P)2] (M = Rh, Ir) and reached a maximum yield of 11% after 3.5 hours when the rhodium complex was used (Figure 1). James and Ochiai (13) have cited spectral evidence for hydroperoxide intermediates, and Fusi et ah (14) obtained evidence which supports the intermediacy of an allylic hydroperoxide during cyclohexene oxidation in the presence of metal complexes. The allylic hydroperoxide (III) which is formed during the oxidation of TME in the presence of [MCl(CO) (Ph3P)2]... 

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