Diol epoxides reaction mechanism

The hydrolysis of epoxides is a eonvenient method for the preparation of vic-diols. The reaction is catalyzed by acids or bases (see discussion of the mechanism on p. 462). Among acid catalysts the reagent of choice is perchloric acid, since side... 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

The existence of isomeric polycyclic aromatic diol epoxide compounds provides rich opportunities for attempting to correlate biological activities with the physico-chemical reaction mechanisms, and conformational and biochemical properties of the covalent DNA adduct8 which are formed. 

The high reactivity of bay-region (and fjord-region) diol epoxides has intrigued chemists for years. Numerous experimental and computational studies have been carried out, affording a wealth of information on the mechanisms by which bay-region diol epoxides form adducts with nucleic acids and are deactivated by reaction with protective nucleophiles or by hydrolysis. Indeed, the hydration of diol epoxides forms unreactive tetrahydroxy metabolites known as tetrols (10.39, Fig. 10.14,a). 

The oxidation of olefins by chromylchloride has been known since the 19th century. Even in the absence of peroxides, this reaction yields epoxides rather than diols in a complex mixture of products, which also contains cfv-chlorohydrins and vicinal dichlorides. Many different reaction mechanisms have been proposed to explain the great variety of observed products, but none of the proposed intermediates have been identified. Stairs favors a direct interaction of the alkene with one oxygen atom of chromylchloride,139-141 while Sharpless proposed a chromaoxetane10 that forms via a [2 + 2]-pathway, a proposal which has led to intense discussions. 

The pH-independent reaction of diol epoxide 81 is quite different from that of diol epoxide 80, although their chemical structures are similar. Subtle differences in conformation clearly are sufficient to cause different pH-independent mechanisms. Whereas one of the pH-independent reaction pathways of 80 involves a carbocation intermediate, carbocation 83 cannot be detected in the pH-independent reaction of 81.89 The mechanism of the diol-forming reactions in the pH-independent reactions of 81 are not clear, but may involve concerted reactions of 81 with solvent. 

A more complicated pH-rate profile is also observed for the hydrolysis reactions of benzo[a]pyrene diol epoxide epoxide 80, and is shown in Fig. 5.102 This profile shows Regions A-D that are similar to those for reaction of precocene I oxide 76 (Fig. 4), except that Region B reaches a full plateau that extends from pH 5 to 9 in water. The interpretation of this pH-rate profile is essentially the same as the interpretation of the profile for hydrolysis of precocene I oxide (Fig. 4). The pH-independent reaction of 80 in Region B (discussed in detail in Section Benzylic epoxides and arene oxides ) yields 60% tetrols in a stepwise mechanism involving a carbocation intermediate and 40% ketone from a completely separate pathway (Scheme 31). The negative inflection of the profile at pH 10-11.5 indicates that hydroxide ion reacts as a base with the intermediate carbocation to reform diol epoxide 80 and thus slow the reaction rate. There is a corresponding increase in the yield of ketone 107 at pH >11. 

The pH-rate profile for diol epoxide 81 does not exhibit a negative inflection in the intermediate pH region similar to that for diol epoxide 80, and its pH-independent reaction does not proceed via an intermediate carbocation, even though the carbocation formed from reaction of this epoxide with H + has a sufficient lifetime to be detected.88 Tetrol products from the pH-independent reaction of 81 must occur by some other mechanism(s), possibly concerted. 

Scheme 40 shows the mechanism of reaction of diol epoxide 81 in solutions containing chloride, bromide or iodide salts.113 At sufficiently low pH, fcH[H + ] is the dominant term of the rate equation, and 81 reacts with H + to form carbocation 83. Carbocation 83 partitions between reaction with water (ks) and capture by halide ion (A 2[X-]). Iodide ion reacts with 83 at or near the diffusion-controlled limit, and is 3-4 times more reactive than bromide ion and 28 times more reactive than chloride... 

At somewhat higher pH, direct nucleophilic attack of halide ion on diol epoxide 81 (fci[X-]) becomes important, and a rate plateau is reached in which this term is the main one. If the pH is sufficiently low, the pH-dependent equilibrium between halohydrin 131 and diol epoxide 81 (shown in Scheme 41) favors halohydrin, which reacts via an SnI reaction (k3) to form tetrols 129. As the pH is increased, however, the pH-dependent equilibrium between halohydrin 131 and diol epoxide 81 shifts to favor diol epoxide, and there is a resulting rate decrease that gives an inflection point in the pH-rate profile at intermediate pH that resembles those in the profiles in Figs 4 and 5. Rate and product observations are rationalized by the mechanism of Scheme 40, and comparable mechanisms can be expected for reactions of other epoxides susceptible to reaction with nucleophiles. 

DNA Lesions Derived from the Reactions of PAH Diol Epoxides with DNA are Excellent Substrates for Probing the Mechanisms of NER... 

Epoxidation and Dihydroxylation of Alkenes There are several ways to convert alkenes to diols. Some of these methods proceed by syn addition, but others lead to anti addition. An important example of syn addition is osmium tetroxide-catalyzed dihydroxylation. This reaction is best carried out using a catalytic amount of OSO4, under conditions where it is reoxidized by a stoichiometric oxidant. Currently, the most common oxidants are f-butyl hydroperoxide, potassium ferricyanide, or an amine oxide. The two oxygens are added from the same side of the double bond. The key step in the reaction mechanism is a [3 + 2] cycloaddition that ensures the syn addition. 

The oxidative functionalization of olefins mediated by transition metal oxides leads to a variety of products including epoxides, 1,2-diols, 1,2-aminoalcohols, and 1,2-diamines [1]. Also the formation of tetrahydrofurans (THF) from 1,5-dienes has been observed, and enantioselective versions of the different reactions have been developed. Although a lot of experimental data has been available, the reaction mechanisms have been a subject of controversial discussion. Especially, osmium (VIII) complexes play an important role there, as the proposal of a stepwise mechanism [2] for the dihydroxylation (DH) of olefins by osmium tetroxide (OSO4) had started an intense discussion about the mechanism [2—11],... 

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