Substrate autoxidation

The free-radical substitution of H for OOH in alkanes is called autoxidation. ( Autoxidation is a misnomer, because the substrate is not oxidizing itself O2 is oxidizing the substrate ) Autoxidation proceeds by a free-radical chain mechanism. Note that the mechanism for oxidation includes a very rare radical-radical combination step in the propagation part. The radical-radical combination step doesn t terminate the chain in this particular reaction because O2 is a... 

Many hydroperoxides have been prepared by autoxidation of suitable substrates with molecular oxygen (45,52,55). These reactions can be free-radical chain or nonchain processes, depending on whether triplet or singlet oxygen is involved. The free-radical process consists of three stages ... 

Autoxidations are usually carried out neat (with substrate as solvent), in a nonoxidizable solvent, or in an aqueous emulsion of the substrate. 

As was noted by Jones (ref. 12) the success of a metal bromide as a catalyst for alkylaromatic autoxidations depends on the ability of the metal to transfer rapidly and efficiently oxidizing power from various autoxidation intermediates onto bromide ion in a manner which generates Br-. The fact that no free bromine is observable in this system is consistent with rapid reaction of intermediate bromine atoms with the substrate. Inhibition of the reaction by cupric salts can be explained by the rapid removal of Br2 or ArCH2- via one-electron oxidation by Cu (Fig. 10). 

As noted earlier, the Amoco catalyst system has been applied to the autoxidation of a wide variety of, mainly methylaromatic, substrates (ref. 19). It has also been applied to the oxidation of other alkylaromatics, e.g. the oxidation of m-phenoxyethylbenzene to the pharmaceutical intermediate, m-phenoxyaceto-phenone (2). 

The Pacman catalyst selectively oxidized a broad range of organic substrates including sulfides to the corresponding sulfoxides and olefins to epoxides and ketones. However, cyclohexene gave a typical autoxidation product distribution yielding the allylic oxidation products 2-cyclohexene-l-ol (12%) and 2-cyclohexene-1-one (73%) and the epoxide with 15% yield [115]. 

Kinetic data exist for all these oxidants and some are given in Table 12. The important features are (i) Ce(IV) perchlorate forms 1 1 complexes with ketones with spectroscopically determined formation constants in good agreement with kinetic values (ii) only Co(III) fails to give an appreciable primary kinetic isotope effect (Ir(IV) has yet to be examined in this respect) (/ ) the acidity dependence for Co(III) oxidation is characteristic of the oxidant and iv) in some cases [Co(III) Ce(IV) perchlorate , Mn(III) sulphate ] the rate of disappearance of ketone considerably exceeds the corresponding rate of enolisation however, with Mn(ril) pyrophosphate and Ir(IV) the rates of the two processes are identical and with Ce(IV) sulphate and V(V) the rate of enolisation of ketone exceeds its rate of oxidation. (The opposite has been stated for Ce(IV) sulphate , but this was based on an erroneous value for k(enolisation) for cyclohexanone The oxidation of acetophenone by Mn(III) acetate in acetic acid is a crucial step in the Mn(II)-catalysed autoxidation of this substrate. The rate of autoxidation equals that of enolisation, determined by isotopic exchange , under these conditions, and evidently Mn(III) attacks the enolic form. 

Second-derivative spectrophotometry has been used to monitor the time-dependent production of cis,tmns-(Xmax 242 nm) and trans, tram- (Xmax 232 nm) diene conjugates of microsomal PUFAs following the exposure of rats to carbon tetrachloride (CCU) (Corongui et al., 1986). These signals have been postulated to be derived from mixtures of peroxidized substrates. Previous studies using chemical model systems have established that autoxidation of linolenic or arachidonic acid results in the production of cis, trans- and tmns, trawr-conjugated diene... 

The autoxidation of aldehydes, and of other organic compounds, may be lessened considerably by very careful purification—removal of existing peroxides, trace metal ions, etc.—but much more readily and effectively by the addition of suitable radical inhibitors, referred to in this context as anti-oxidants. The best of these are phenols and aromatic amines which have a readily abstractable H atom, the resultant radical is of relatively low reactivity, being able to act as a good chain terminator (by reaction with another radical) but only as a poor initiator (by reaction with a new substrate molecule). 

Recently, we have demonstrated another sort of homogeneous sonocatalysis in the sonochemical oxidation of alkenes by O2. Upon sonication of alkenes under O2 in the presence of Mo(C0) , 1-enols and epoxides are formed in one to one ratios. Radical trapping and kinetic studies suggest a mechanism involving initial allylic C-H bond cleavage (caused by the cavitational collapse), and subsequent well-known autoxidation and epoxidation steps. The following scheme is consistent with our observations. In the case of alkene isomerization, it is the catalyst which is being sonochemical activated. In the case of alkene oxidation, however, it is the substrate which is activated. 

The early practical application of antioxidants was connected with the development of rubber production. The rubber is easily oxidized in air, and the first antioxidants were empirically found and used to stabilize it [1]. Empirical search for antioxidants was performed by Moureu and Dufresse [2] during the First World War. These researchers successfully solved the problem of acrolein stabilization by the addition of hydroquinone. They explained the retarding action of the antioxidant in the scope of peroxide conception of Bach and Engler (see Chapter 1). They proposed that the antioxidant rapidly reacts with the formed hypothetical moloxide and in such a way prevents the autoxidation of the substrate. 

Catalysis by radicals will usually be due to a radical addition or displacement reaction, hydrogen and halogen being the atoms on which the displacement most often occurs. It is usually a chain reaction once the substrate is converted into a radical it carries the reaction to many molecules of substrate. Examples are polymerization and autoxidation. 

Metal ions play an important role as catalysts in many autoxidation reactions and have been considered instrumental in regulating natural as well as industrial processes. In these reactive systems, in particular when the reactions occur under environmental or in vivo biochemical conditions, the metal ions are involved in complicated interactions with the substrate(s) and dioxygen, and the properties of the actual matrix as well as the transport processes also have a pronounced impact on the overall reactions. In most cases, handling and analyzing such a complexity is beyond the capacity of currently available experimental, computational and theoretical methods, and researchers in this field are obliged to use simplified sub-systems to mimic the complex phenomena. When the simplified conditions are properly chosen, these studies provide surprisingly accurate predictions for the real systems. In this paper we review the results obtained in kinetic and mechanistic studies on the model systems, but we do not discuss their broad biological or environmental implications. 

A brief overview on why most of the autoxidation reactions develop complicated kinetic patterns is given in Section II. A preliminary survey of the literature revealed that the majority of autoxidation studies were published on a small number of substrates such as L-ascor-bic acid, catechols, cysteine and sulfite ions. The results for each of these substrates will be discussed in a separate section. Results on other metal ion mediated autoxidation reactions are collected in Section VII. In recent years, non-linear kinetic features were discovered in some systems containing dioxygen. These reactions form the basis of a new exciting domain of autoxidation chemistry and will be covered in Section VIII. 

The general features discussed so far can explain the complexity of these reactions alone. However, thermodynamic and kinetic couplings between the redox steps, the complex equilibria of the metal ion and/or the proton transfer reactions of the substrate(s) lead to further complications and composite concentration dependencies of the reaction rate. The speciation in these systems is determined by the absolute concentrations and the concentration ratios of the reactants as well as by the pH which is often controlled separately using appropriately selected buffers. Perhaps, the most intriguing task is to identify the active form of the catalyst which can be a minor, undetectable species. When the protolytic and complex-formation reactions are relatively fast, they can be handled as rapidly established pre-equilibria (thermodynamic coupling), but in any other case kinetic coupling between the redox reactions and other steps needs to be considered in the interpretation of the kinetics and mechanism of the autoxidation process. This may require the use of comprehensive evaluation techniques. 

The model shown in Scheme 2 indicates that a change in the formal oxidation state of the metal is not necessarily required during the catalytic reaction. This raises a fundamental question. Does the metal ion have to possess specific redox properties in order to be an efficient catalyst A definite answer to this question cannot be given. Nevertheless, catalytic autoxidation reactions have been reported almost exclusively with metal ions which are susceptible to redox reactions under ambient conditions. This is a strong indication that intramolecular electron transfer occurs within the MS"+ and/or MS-O2 precursor complexes. Partial oxidation or reduction of the metal center obviously alters the electronic structure of the substrate and/or dioxygen. In a few cases, direct spectroscopic or other evidence was reported to prove such an internal charge transfer process. This electronic distortion is most likely necessary to activate the substrate and/or dioxygen before the actual electron transfer takes place. For a few systems where deviations from this pattern were found, the presence of trace amounts of catalytically active impurities are suspected to be the cause. In other words, the catalytic effect is due to the impurity and not to the bulk metal ion in these cases. 

In non-aqueous solution, the copper catalyzed autoxidation of catechol was interpreted in terms of a Cu(I)/Cu(II) redox cycle (34). It was assumed that the formation of a dinuclear copper(II)-catecholate intermediate is followed by an intramolecular two-electron step. The product Cu(I) is quickly reoxidized by dioxygen to Cu(II). A somewhat different model postulated the reversible formation of a substrate-catalyst-dioxy-gen ternary complex for the Mn(II) and Co(II) catalyzed autoxidations in protic media (35). 

The autoxidation of 3,5-di-terf-butylcatechol (H2DTBC) was frequently used to test the catalytic activity of various metal complexes. Speier studied the reaction with [Cu(PY)Cl] (PY = pyridine) in CH2C12 and CHCI3, and reported second-, first- and zeroth-order dependence with respect to Cu(I), 02 and substrate concentrations, respectively (41). The results are consistent with a kinetic model in which the rate determining oxidation of Cu(I) is followed by fast reduction of Cu(II) by H2DTBC. 

Autoxidation became slower when the pH was decreased. Because the substrate is not involved in the rate-determining steps, its protolytic equilibria cannot account for this observation. A straightforward explanation was not readily available for this observation. 

The catalytic activities of Cu(II), Co(II) and Mn(II) are considerably enhanced by sodium dodecyl sulfate (SDS) in the autoxidation of H2DTBC (51). The maximum catalytic activity was found in the CMC region. It was assumed that the micelles incorporate the catalysts and the short metal-metal distances increase the activity in accordance with the kinetic model discussed above. The concentration of the micelles increases at higher SDS concentrations. Thus, the concentrations of the catalyst and the substrate decrease in the micellar region and, as a consequence, the catalytic reaction becomes slower again. 

The experimental observations were interpreted by assuming that the redox cycle starts with the formation of a complex between the catalyst and the substrate. This species undergoes intramolecular two-electron transfer and produces vanadium(II) and the quinone form of adrenaline. The organic intermediate rearranges into leucoadrenochrome which is oxidized to the final product also in a two-electron redox step. The +2 oxidation state of vanadium is stabilized by complex formation with the substrate. Subsequent reactions include the autoxidation of the V(II) complex to the product as well as the formation of aVOV4+ intermediate which is reoxidized to V02+ by dioxygen. These reactions also produce H2O2. The model also takes into account the rapidly established equilibria between different vanadium-substrate complexes which react with 02 at different rates. The concentration and pH dependencies of the reaction rate provided evidence for the formation of a V(C-RH)3 complex in which the formal oxidation state of vanadium is +4. 

The half-order of the rate with respect to [02] and the two-term rate law were taken as evidence for a chain mechanism which involves one-electron transfer steps and proceeds via two different reaction paths. The formation of the dimer f(RS)2Cu(p-O2)Cu(RS)2] complex in the initiation phase is the core of the model, as asymmetric dissociation of this species produces two chain carriers. Earlier literature results were contested by rejecting the feasibility of a free-radical mechanism which would imply a redox shuttle between Cu(II) and Cu(I). It was assumed that the substrate remains bonded to the metal center throughout the whole process and the free thiyl radical, RS, does not form during the reaction. It was argued that if free RS radicals formed they would certainly be involved in an almost diffusion-controlled reaction with dioxygen, and the intermediate peroxo species would open alternative reaction paths to generate products other than cystine. This would clearly contradict the noted high selectivity of the autoxidation reaction. 

Metal ion catalyzed autoxidation reactions of glutathione were found to be very similar to that of cysteine (76,77). In a systematic study, catalytic activity was found with Cu(II), Fe(II) and to a much lesser extent with Cu(I) and Ni(I). The reaction produces hydrogen peroxide, the amount of which strongly depends on the presence of various chelating molecules. It was noted that the catalysis requires some sort of complex formation between the catalyst and substrate. The formation of a radical intermediate was not ruled out, but a radical initiated chain mechanism was not necessary for the interpretation of the results (76). 

A comparison of the rate constants for the [Cun(FLA)(IDPA)]+-cata-lyzed autoxidation of 4/-substituted derivatives of flavonol revealed a linear free energy relationship (Hammett) between the rate constants and the electronic effects of the para-substituents of the substrate (128). The logarithm of the rate constants linearly decreased with increasing Hammett o values, i.e. a higher electron density on the copper center yields a faster oxidation rate. 

In abroad sense, the model developed for the cobaloxime(II)-catalyzed reactions seems to be valid also for the autoxidation of the alkyl mercaptan to disulfides in the presence of cobalt(II) phthalocyanine tetra-sodium sulfonate in reverse micelles (142). It was assumed that the rate-determining electron transfer within the catalyst-substrate-dioxygen complex leads to the formation of the final products via the RS and O - radicals. The yield of the disulfide product was higher in water-oil microemulsions prepared from a cationic surfactant than in the presence of an anionic surfactant. This difference is probably due to the stabilization of the monomeric form of the catalyst in the former environment. 

Ruthenium (III) was shown to be a potent catalyst for the autoxidation of various organic substrates by Taqui Khan and co-workers (143-148). 

The presence of ascorbic acid as a co-substrate enhanced the rate of the Ru(EDTA)-catalyzed autoxidation in the order cyclohexane < cyclohexanol < cyclohexene (148). The reactions were always first-order in [H2A]. It was concluded that these reactions occur via a Ru(EDTA)(H2A)(S)(02) adduct, in which ascorbic acid promotes the cleavage of the 02 unit and, as a consequence, O-transfer to the substrate. While the model seems to be consistent with the experimental observations, it leaves open some very intriguing questions. According to earlier results from the same laboratory (24,25), the Ru(EDTA) catalyzed autoxidation of ascorbic acid occurs at a comparable or even a faster rate than the reactions listed in Table III. It follows, that the interference from this side reaction should not be neglected in the detailed kinetic model, in particular because ascorbic acid may be completely consumed before the oxidation of the other substrate takes place. 

The enhanced chemiluminescence associated with the autoxidation of luminol (5-amino-2,3-dihydro-1,4-phthalazinedione) in the presence of trace amounts of iron(II) is being used extensively for selective determination of Fe(II) under natural conditions (149-152). The specificity of the reaction is that iron(II) induces chemiluminescence with 02, but not with H202, which was utilized as an oxidizing agent in the determination of other trace metals. The oxidation of luminol by 02 is often referred to as an iron(II)-catalyzed process but it is not a catalytic reaction in reality because iron(II) is not involved in a redox cycle, rather it is oxidized to iron(III). In other words, the lower oxidation state metal ion should be regarded as a co-substrate in this system. Nevertheless, the reaction deserves attention because it is one of the few cases where a metal ion significantly affects the autoxidation kinetics of a substrate without actually forming a complex with it. 

Searching for other oscillatory autoxidation reactions led Druliner and Wasserman to use cyclohexanone as a substrate instead of benzalde-hyde (168). Unlike the simple stoichiometry found for the benzaldehyde reaction, the ketone gives at least six or more products, and the relative amounts of these vary substantially with the experimental conditions (Scheme 7). 

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