Epoxide Ring Opening

Core Concepts

In this tutorial, you will learn about the mechanism, acid-base dependence, and reagents involved in the epoxide ring opening reaction.

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What are epoxide ring openings?

Epoxide ring openings are a valuable reaction in organic synthesis. In brief, these reactions involve an epoxide, which is a 3-membered ring containing oxygen, “breaking” one of its C-O bonds in response to a nucleophilic attack. A typical epoxide ring opening is shown below, with sodium methoxide serving as the nucleophile.

epoxide ring opening example

Epoxide ring openings proceed similarly to nucleophilic substitution reactions, but because the oxygen is bonded to two carbons, it remains attached to the structure and forms an alcohol upon protonation. This is different from most nucleophilic substitutions, which involve a “leaving group” that separates from the parent molecule.

These reactions are important because epoxides are relatively easy to generate and require mild conditions to react. Additionally, as we will discover, the formation of epoxide ring opening products can be tightly controlled based on solvent pH.


Many different nucleophiles can be used in epoxide ring openings. Some examples include:

Substitution Products

The most important consideration in epoxide ring openings is the stability of the intermediate. Acidic solutions provide favorable, more stable reaction mediums for these reactions than basic conditions, leading to differences in products based on solvent. Let us first consider the reaction of epoxide rings in basic conditions.

Basic Conditions

Under basic conditions, an asymmetric epoxide (where each carbon contains a different number of constituents) will undergo attack from the nucleophile at the less substituted carbon. This is due to the steric hindrance of the more substituted carbon. The oxygen anion will serve as the “leaving group”, which is extremely strong and high energy. Protonation with an acid, or simply the use of a polar protic solvent will result in the alcohol product and a stabilized oxygen.

Acidic Conditions

Under Acidic conditions, an asymmetric epoxide will undergo attack at the more substituted carbon. This occurs due to the difference in mechanism between acidic and basic conditions. In acidic conditions, the oxygen within the epoxide ring becomes protonated, allowing it to be a more stable “leaving group” upon the substitution reaction. The proton positively charges the epoxide group and weakens the bond between the oxygen and the substituted carbon. This is due to the carbocation stability rules, which state that more substituted carbons are more stable when positively charged.

Consequently, the bond between the protonated oxygen atom and the more substituted carbon begins to break, concentrating the positive charge on the more substituted carbon. A full carbocation does not form, so there is no racemic mixture after nucleophilic attack. A typical reaction can be seen below.

Acidic conditions only allow weak bases to be used, however, as this reaction more closely resembles an SN1 than an SN2. Using strong bases in acidic conditions will result in no reaction of the molecule of interest because the main reaction will just be protonation of the nucleophile. Therefore, in acidic conditions, weak nucleophiles are used and undergo substitution at the more substituted carbon.


Epoxide rings are often a part of a larger molecule, and hence, the stereochemistry of the substituted carbons becomes an important consideration.

Under most epoxide ring opening reactions, the nucleophile will undergo a backside attack, as the carbon-oxygen bond serves as the leaving group. This will result in a product with the alcohol group antiperiplanar, or facing opposite, to the nucleophile. This occurs under both acidic and basic conditions, as there is always only one side for the nucleophile to attack, due to the blocking of the carbon-oxygen bond. This keeps the stereocenter chirality and preserves the wedges and dashes of substituted constituents.

Symmetrical Epoxides

Symmetric epoxide ring openings will result in a mix of enantiomers. This is due to the equal likelihood of a nucleophile to attack either carbon involved in the epoxide ring.

Ring stereochemistry

One other important consideration is the stereochemistry of a ring in a larger molecule. While the bond-line structures shown previously in this article may show rings as in-plane with the two carbon atoms at the base, in a larger molecule the oxygen molecule is actually on a wedge or dash in comparison to the carbons as shown below.

This is important to consider to maintain stereochemistry upon ring opening.

Epoxide Ring Opening Practice Problems

Problem 1

Complete the following reaction

epoxide ring opening practice problem 1

Problem 2

The main product of the following reaction is shown below. Explain, given the reagents, why this substitution is favored.

epoxide ring opening practie problem 2

Epoxide Ring Opening Practice Problem Answers

Problem 1

epoxide ring opening practice problem 1 solution

Problem 2

Given that this is an acid-catalyzed epoxide ring opening, the more substituted carbon would usually be the site of nucleophilic attack. However, both carbons here are equally as substituted. Therefore, the characteristics of functional groups beyond the carbons of the ring must be the cause of the favored substitution. One carbon is bonded to a methyl while the other is bonded to an ethylene. The delocalized electron stabilizes the partial positive carbon better than the methyl group. Therefore, this is the more favored product.