11.9:
Preparation of Epoxides
Epoxides are prepared by the oxidation of alkenes using various oxidizing agents, and the reaction is known as epoxidation.
Some of the most common oxidizing agents are peroxy acids, such as meta-chloroperoxybenzoic acid or mCPBA.
Peroxy acids are unique in having an electrophilic oxygen atom in the carboxylic group, which acts as the center for nucleophilic attacks.
Consider the oxidation of cis-2-butene using mCPBA to give cis-2,3-dimethyloxirane, with the mCPBA itself getting reduced to 3-chlorobenzoic acid.
The reaction proceeds via a cyclic transition state, wherein the alkene's π bond acts as a nucleophile and attacks the electrophilic oxygen of the peroxy acid to form the first carbon–oxygen bond of the epoxide.
Simultaneously, the oxygen–oxygen bond of the peroxy acid breaks, forming a new carbonyl bond.
Further, the π-electrons of the peroxy acid's original carbonyl bond abstract a proton from the OH bond to form a new OH bond. The oxygen then attacks the other carbon of the alkene, forming the second carbon–oxygen bond.
Overall, the electrophilic oxygen from the peroxy acid gets transferred to the double bond of the alkene, thus forming the epoxide ring. Since all the bond-breaking and bond-making occurs in a single step, the reaction is said to be concerted.
Stereospecifically, the epoxide ring installation on the alkene follows syn addition. Hence, a cis-alkene gives a cis-epoxide, and a trans-alkene gives a trans-epoxide.
Moreover, alkene's planar structure facilitates the nucleophilic attack and the formation of the epoxide ring from either face, yielding a meso compound for the cis– and a racemic mixture for the trans-epoxide.
Halohydrins of alkenes, when treated with a base, can also form epoxides. The reaction is an intramolecular variation of the Williamson ether synthesis.
Consider the cyclization of 3-chloro-2-butanol, a halohydrin derived from cis-2-butene, to give cis-2,3-dimethyloxirane.
The reaction proceeds via the deprotonation of halohydrin's hydroxyl group by the base to form the alkoxide ion, a nucleophile.
Typical of an SN2 reaction, the nucleophile attacks from the backside and displaces the chloride ion on the adjacent carbon forming the oxirane ring. Consequently, the epoxide formed retains the alkene stereospecificity.
11.9:
Preparation of Epoxides
Overview
Epoxides result from alkene oxidation, which can be achieved by a) air, b) peroxy acids, c) hypochlorous acids, and d) halohydrin cyclization.
Epoxidation with Peroxy Acids
Epoxidation of alkenes via oxidation with peroxy acids involves the conversion of a carbon–carbon double bond to an epoxide using the oxidizing agent meta-chloroperoxybenzoic acid, commonly known as MCPBA. Since the O–O bond of peroxy acids is very weak, the addition of electrophilic oxygen of peroxy acids to alkenes occurs with ease, thereby following syn addition. Hence, the epoxides are produced with the retention of the alkene configuration.
Epoxidation via Air Oxidation
Although peroxy-mediated epoxidation is the most common method for alkene oxidation, ethylene oxide is synthesized at the industrial scale via air oxidation by treating a mixture of ethylene and air in the presence of a silver catalyst.
Cyclization of Halohydrins
Cyclization of halohydrins of alkenes in the presence of a base also yields epoxides, and the reaction follows the SN2 substitution mechanism. Hence, the nucleophile—the oxygen anion—and the leaving group—the chloride ion—must orient anti to each other in the transition state to make the halohydrins cyclization feasible.
In noncyclic halohydrins, this anti-relationship is achieved by an internal rotation. For instance, in 1-chloro-2-methyl-2-propanol, shown in Figure 1, the hydroxyl and the chloro group are not oriented anti to each other. To achieve the anti-relationship, the carbon-bearing chloro group undergoes an internal rotation, thereby making the nucleophile attack—from the backside of the C–X bond—and the ejection of the leaving group feasible. Thus, the epoxides formed via halohydrin cyclization also retain the alkene configuration.
Similarly, the cyclic halohydrins must undergo conformational changes to achieve the anti-relationship. For example, the halohydrin of cyclohexane, shown in Figure 2, undergoes a conformational change from diequatorial to diaxial to successfully form an epoxide.
Suggested Reading
- Brown, W.H., & Iverson, B.L., & Anslyn, V.E., & Foote S.C. (2014). Organic Chemistry. Mason, Ohio: Cengage Learning, 118-123.
- Loudon, M., & Parise, J. (2016). Organic Chemistry. New York, NY: Macmillan Publishers, 230-234.