Overview of the Reactions of Epoxides

Summary

• Epoxides are much more reactive than simple ethers due to ring strain.
• Nucleophiles attack the electrophilic C of the C-O bond causing it to break, resulting in ring opening.
• Opening the ring relieves the ring strain.
• The products are typically 2-substituted alcohols.
• Epoxides can react with a large range of nucleophiles.

• Stronger nucleophiles (anionic e.g. alkoxides, Grignard reagents etc.)

• Examples of such nucleophilic systems are :  RMgX, RLi, RCºCM, LiAlH₄, NaBH4

• Weaker nucleophiles (neutral e.g. water) can be made to react with epoxides in the presence of acid catalysts.

• Examples of such nucleophilic systems are :  H₂O, ROH, R-NH2

S_N2 type Reactions of Epoxides

• Reactive nucleophiles react with epoxides in an S_N2 type of reaction.
• Reactive nucleophiles are usually anions so the reaction conditions are essentially basic.
• Examples of such nucleophilic systems are :  RMgX, RLi, RCºCM, LiAlH4, HO^-, RO^-
• The leaving group is the oxygen atom of the epoxide in the form of the alkoxide which is converted to the alcohol on an acidic work-up.
• For non-symmetrical epoxides, there is a question of regioselectivity :

Scenario 1: The Nu attacks the more substituted C of the epoxide at 180o to the C-O bond that breaks.
Scenario 2: The Nu attacks the least hindered end of the epoxide at 180o to the C-O bond that breaks.

• Experimental results show that scenario 2 is observed by stronger nucleophiles such as Grignard reagents, RMgBr.
• Recall that S_N2 reactions of alkyl halides follow the order CH₃-  >  1^o  >  2^o  (i.e. favors the less substituted system)
• Reactive nucleophiles attack the least hindered end of the epoxide in an S_N2 type fashion at 180^o to the leaving group bond.
• This results in the formation of the more substituted alcohol.

• Under basic conditions, epoxides open in an "S_N2 like" fashion with the nucleophile attacking the less substituted end.

S_N1 type Reactions of Epoxides

• Before weaker nucleophiles react with epoxides the epoxide must first be protonated so the reaction conditions are acidic.
• Protonation makes the epoxide more electrophilic and creates a better leaving group.
• Examples of  nucleophiles requiring this approach : H₂O, ROH etc.
• The leaving group is the protonated oxygen atom of the epoxide in the form of a neutral alcohol.
• Typically the nucleophile is then deprotonated to give a neutral product.
• For non-symmetrical epoxides, there is a question of regioselectivity :

Scenario 1: The Nu attacks the more substituted C of the epoxide at 180o to the C-O bond that breaks.
Scenario 2: The Nu attacks the least hindered end of the epoxide at 180o to the C-O bond that breaks.

• Experimental results show that scenario 1 is observed under these weaker nucleophiles such as water or alcohols.
• Recall that S_N1 reactions of alkyl halides follow the order 3^o  >  2^o  >  1^o  (i.e. favors the more stable carbocation)
• In order to appreciate this type of reaction we should consider what happens if we break each of the C-O bonds....

• If the more stable carbocation is favored then the nucleophile attacks the more substituted end of the epoxide.
• This results in the formation of the less highly substituted alcohol.
• Note that although the carbocation does not usually form the carbocation character is important.

In reality it is usually that the epoxide C-O bond to the more substituted center is weaker resulting in carbocation character at that C and the nucleophile attacks there.... because the C-O bond is not totally broken when the nucleophile attacks, it still attacks at 180o with respect to the leaving group.

• This is best described as an S_N1 type of reaction since carbocation character is involved.

• Under acidic conditions, epoxides open in an "S_N1 like" fashion with the nucleophile attacking the more substituted end.