Arene oxides with nucleophiles

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. 

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. 

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. 

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... 

Keller and Heidelberger131 reported the kinetics of solvolysis of 1, 30, 38, and benz[a,/i]anthracene 5,6-oxide (228). These studies were carried out mostly in the pH < 7 region where nucleophilic addition ordinarily does not take place with either K-region or non-K-region epoxides. These authors found evidence for the formation of a carbonium ion and consequently were led to believe that the cell macromolecules react with arene oxides through a carbonium ion-trapping mechanism and not by a direct nucleophilic displacement on the 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... 

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. 

Electron-donating substituents direct the incoming nucleophile predominantly to the meta-position and electron-withdrawing substituents to the ortho-position. Oxidative demetallation (DDQ, iodine) is applied to reoxidize the cyclohexadienyl ligand, releasing a substituted arene. Addition of nucleophiles to halobenzene-FeCp complexes leads to nucleophilic substitution of the halo substituent (Scheme 1.34). Demetallation of the product complexes is achieved by irradiation with sunlight or UV light in acetone or acetonitrile. 

A regioselective and highly syn-stereoselective catalyst-free intermolecular alkylation of aryl borates with aryl epoxides under mild, neutral conditions has been reported.27 The reaction of /ra .s-stilbene oxide with tri(3,5-dimethylphenyl)borate gave a 38% yield (>95% syn) of the C-alkylated product (13), easily separated from (g) the O-alkylated product(s). Triflic anhydride has been used to activate enones to nucleophilic attack by electron-rich arenes in the presence of a sterically hindered base.28 Resorcinol dimethyl ether, for example, reacted with cyclohex-2-en-l-one to... 

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. 

Not only alkenes and arenes but also other types of electron-rich compound can be oxidized by oxygen. Most organometallic reagents react with air, whereby either alkanes are formed by dimerization of the metal-bound alkyl groups (cuprates often react this way [80]) or peroxides or alcohols are formed [81, 82]. The alcohols result from disproportionation or reduction of the peroxides. Similarly, enolates, metalated nitriles, phenolates, enamines, and related compounds with nucleophilic carbon can react with oxygen by intermediate formation of carbon-centered radicals to yield dimers (Section 5.4.6 [83, 84]), peroxides, or alcohols. The oxidation of many organic compounds by air will, therefore, often proceed faster in the presence of bases (Scheme 3.21). 

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