Regioselectivity of Ring Opening

The regioselectivity of epoxide ring opening by CH3O in methanol is controlled by the same features as the S 2 displacement reactions we considered in Chapter 10. The nucleophilic methoxide anion regioselectively attacks the least hindered carbon atom. That is, it attacks the primary rather than the tertiary carbon atom of 2,2-dimethyloxirane in the rate-determining step. This intermediate alkoxide then abstracts a proton from the solvent in a rapid second step that regenerates the methoxide base. 

The regioselectivity is different for the reaction of the same epoxide with methanol in acid. The first step is a rapid reversible protonation of the epoxide. The epoxide then reacts with the nucleophile methanol in the rate-determining step. Subsequently, the protonated product reversibly transfers a proton to the solvent. 

The mechanism for the acid-catalyzed ring opening differs from the base-catalyzed reaction in one important way that explains why the nucleophile now attacks the more hindered carbon atom. The structure of the protonated substrate that reacts with the nucleophile in the rate-determining step can exist in three resonance forms. 

Because a positive charge is more stable on the tertiary carbon atom than on the primary carbon atom, the tertiary carbocation resonance form is a more important contributor to the resonance hybrid than the primary carbocation. This uneven charge distribution accounts for the difference in the energy barriers for the formation of the two possible isomeric products. Nucleophihc attack at the carbon atom with the greater positive charge is favored. That is, it has the lower energy barrier. This stabilization of charge overrides the effect of steric hindrance, which disfavors attack at the tertiary center. 

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The regioselectivity of ring opening of 4a-c is successfully controlled by the choice of reaction conditions. Lewis acid in dichloromethane and hydrogen chloride in alcohol are suitable conditions for generation of an alkylideneallyl cation, which was employed for studying its reactivity with nucleophiles such as... 

Table 2 Regioselectivity (%) of ring-opening reactions of trans-oxiranes.

The regioselectivity of ring opening of tri- and tetrahalocyclopropanes has been determined, e.g., ring opening of 12 to 13. ... 

Bucciarelli, M., Fomi, A., Moretti, I. et al. (1995) Regioselectivity of ring-opening reactions of optically active N-acetyl-2-methoxycarbonylaziridine. Tetrahedron Asymmetry, 6, 2073-2080. 

There is an important difference in the regioselectivity of ring-opening reactions of epoxides in acid solution compared with their counterparts in base. Unsymmetrically substituted epoxides tend to react with anionic nucleophiles at the less hindered carbon of the ring. Under acid-catalyzed conditions, however, reaction occurs at the more substituted carbon. 

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