Nucleophiles, reaction with arene oxides

Detailed studies by Bruice, Jerina, and co-workers, referred to earlier, showed that three factors determine whether nucleophilic reaction of tissue materials with arene oxides occur directly. They are (a) the structure of the... 

Two important reactions of arene oxides in animal tissue are (1) detoxification and (2) formation of conjugates of arene oxides with purine pyrimidine bases of DNA. For both of these reactions to take place, the arene oxide should have a certain intrinsic stability to survive an aromatization reaction. Reaction with the thiolate bond of glutathione is responsible for detoxification, whereas the extent of involvement of arene oxides in the nucleophilic reactions with nonpolarized nitrogen bases of DNA is directly related to their carcinogenic activity. 

The reaction is highly regio- and stereospecihc, always proceeding with inversion of configuration. With arene oxides, this means that only tranx-dihydrodiols are formed. All of the experimental evidence points to a general base-catalyzed nucleophilic (S,v2) addition of water to the oxirane ring. 

In general, nucleophilic addition reactions of arene oxides with nonpolarizable oxygen and nitrogen nucleophiles are very slow. Thus both NH3 and NHj nucleophiles failed to add to benzene oxides under a range of conditions. Amine nucleophiles have, however, been found to react very slowly with benzene oxide. 

The reactions of strong carbon nucleophiles with arene oxides 1 and 11 leads to rapid adduct formation.Methyl lithium and dimethyl magnesium react with arene oxide 1 by 1,6-addition to give ds-adducts. Trans-adducts were also obtained from reaction of dimethyl magnesium and methyl lithium with arene oxides 1 and 11, respectively, by the more usual 1,2-trans addition mechanism. ... 

Arenes, on complexdQon with Cr, Fe, Mn, and so forth, acquire strongly electrophilic character, such complexes m reactions with nucleophiles behave as electrophilic tutroarenes. Synthesis of aromatic tutnles via the temporary complexanon of rutroarenes to the catiotuc cyclopentadienyhron moiety, cyarude addition, and oxidative demetalation v/ith DDQ has been reported fEq. 9.43 ... 

The intracellular nucleophile glutathione (GSH y-Glu-Cys-Gly) acts as a protective mechanism against electrophilic insults and may be present at concentrations of up to 10 mM [26]. The reaction of glutathione with a non-polar compound bearing an electrophilic carbon, nitrogen or sulfur atom may be mediated enzymatically by glutathione-S-transferase (GST), with typical substrates being species such as arene oxides, quinones and a,P-unsaturated carbonyl compounds. 

The K-region oxides undergo nucleophilic addition with OH", C032", water, amines, and mercaptides.88,140 The second-order rate constants for the reactions of OH", water, and primary and secondary amines with 1 at 30°C and with ethylene oxide at 25°C141 can be simply related by Eq. (6),2 which shows that the sensitivity of the two oxides to the nature of the nucleophile is similar and that the arene oxide is more reactive. 

Very recently, the reaction of styrene 3,4-epoxide (245) with ethyl mercaptan has been reported.148 A mixture of 2-, 3-, and 4-ethylthiostyrenes is formed in the ratio of 1 9 7 along with small amounts (18%) of 4-vinylphenol. These results can be explained as nucleophilic attack on the intact arene oxide and the reaction of the zwitterion formed by the spontaneous reaction. 

Arenes usually undergo electrophilic substitution, and are inert to nucleophilic attack. However, nucleophile attack on arenes occurs by complex formation. Fast nucleophilic substitution with carbanions with pKa values >22 has been extensively studied [44]. The nucleophiles attack the coordinated benzene ring from the exo side, and the intermediate i/2-cvclohexadienyl anion complex 171 is generated. Three further transformations of this intermediate are possible. When Cr(0) is oxidized with iodine, decomplexation of 171 and elimination of hydride occur to give the substituted benzene 172. Protonation with strong acids, such as trifluoroacetic acid, followed by oxidation of Cr(0) gives rise to the substituted 1,3-cyclohexadiene 173. The 5,6-trans-disubstituted 1,3-cyclohexadiene 174 is formed by the reaction of an electrophile. 

The yellow CpFe1 (//6-arene) salts (most commonly BF4 or PF6 ) are usually stable up to at least 200 °C, are stable in concentrated sulfuric acid, and are very resistant towards oxidation (until recently, it was believed that they could not be oxidized [23] vide infra). They are not easy to reduce either [23] (vide infra). The chloride salts [CpFe+( f -arene) Cl- are water-soluble they are formed upon hydrolysis following ligand-exchange reactions between ferrocene and the arene in the presence of aluminum chloride [21]. Such aqueous solutions may sometimes be directly used for nucleophilic reactions [22] (vide infra). The BF4- salts are also sometimes quite soluble in water, but the PF6- salts are much less so. Electrophilic reactions that are readily undergone by the free arenes, such as Friedel-Crafts reactions, are no longer possible on the CpFe+( /6-arene) complexes [19, 23]. On the other hand, a range of nucleophilic reactions that are impossible or very difficult to carry out with free arenes become possible under ambient or mild conditions with the CpFe+()/6-arene) complexes (Scheme 2) [16-20]. 

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