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Overview

Epoxides are compounds containing the three-membered ring:

They are ethers (see Unit 15: Ethers), but the three-membered ring gives them unusual properties which make them an exceedingly important class of compounds. Epoxides are commonly made by the oxidation of alkenes by peroxy compounds, such as benzoic acid:

When allowed to stand in ether or chloroform solution, the peroxy acid and the unsaturated compound -- which need not be a simple alkene -- react to yield benzoic acid and the epoxide. For example:

Epoxides owe their importance to the ease of opening of the highly strained three-membered ring. They undergo acid-catalyzed reactions with extreme ease and -- unlike ordinary ethers -- can even be cleaved by bases.

A polymer made of epoxide units is called a polyepoxide or an epoxy. Epoxy resins are used as adhesives and structural materials; one such example is epoxyethane.

I. Acid-catalyzed Cleavage  

Like other ethers, an epoxide is protonated by acid.

The protonated epoxide can then undergo attack by any number of nucleophilic reagents.                            

An important feature of the reactions of epoxides is the formation of compounds that contain two functional groups. Thus, reaction with water yields a 1,2-diol. Reaction with an alcohol yields a compound that is both ether and alcohol.

The two-stage process of epoxidation followed by hydrolysis is stereoselective, and gives 1,2-diols corresponding to anti-addition to the C=C double bond. The same stereochemistry was observed for hydroxylation of alkenes by formic acid. There, an epoxide is formed as a reaction intermediate which is rapidly cleaved in the acidic medium. The interpretation is exactly the same as that given to account for anti-addition of halogens. Indeed, epoxides and their hydrolysis served as a model on which the halonium ion mechanism was patterned.  

II. Base-catalyzed Cleavage  

Unlike ordinary ethers, epoxides can be cleaved under alkaline conditions. Here it is the epoxide itself -- not the protonated epoxide -- which undergoes nucleophilic attack.

The lower reactivity of the non-protonated epoxide is compensated for by the more basic, more strongly nucleophilic reagents that are compatible with the alkaline solution (e.g. alkoxides, phenoxides, ammonia, etc.).

Like alkyl halides and sulfonates, and like carbonyl compounds, epoxides are an important source of electrophilic carbon -- of carbon that is highly susceptible to attack by a wide variety of nucleophiles. (E.G. Epoxides generated form carcinogenic hydrocarbons are even attacked by the nucleophilic portion of the genetic material DNA and thereby induce mutation and tumors).  

III. Cleavage Orientation

There are tow C atoms in an epoxide ring. In principle, either one can suffer nucleophilic attack. In a symmetrical epoxide like ethylene oxide, the two carbons are equivalent, and attack occurs randomly at either site. But in an asymmetrical epoxide molecule, the C atoms are not equivalent, and the product obtained depends upon which one is preferentially attacked.

It turns out that the preferred point of attack depends chiefly on whether the reaction is acid-catalyzed or base-catalyzed. Consider, for example, two reactions of isobutylene oxide:

Here (as in general) the nucleophile attacks the more substituted carbon in an acid-catalyzed cleavage, and the less substituted carbon in a base catalyzed cleavage.

Our first thought might be that there are two different reaction mechanisms (e.g. SN1 vs. SN2). But the evidence indicates clearly that both are of the SN2 type. This is characterized typically by cleavage of the C-O bond and attack by the nucleophile in a single step.

How, then, are we to account for the difference in orientation -- particularly for the SN2 attack at the more hindered position in acid-catalyzed cleavage ?

The answer to this query lies in the transition state (or reaction intermediate).

In the transition state of most SN2 reactions, bond-breaking and bond-making have proceeded to about the same extent, and carbon has not become appreciably positive or negative. Therefore steric factors, not electronic factors, chiefly determine reactivity.

But in acid-catalyzed cleavage of an epoxide, the C-O bond, already weak because of the angle strain of the three-membered ring, is further weakened by protonation. The leaving group is a very good one -- the weakly basic alcohol hydroxyl (OH) group. Alternatively, the nucleophile is a poor one (e.g. water, alcohol). In the transition state, bond-breaking has proceeded further than bond-making, and thus carbon has acquired a considerable positive charge.

Since both leaving group and nucleophile are far away, crowding is relatively unimportant here. The stability of the transition state is determined chiefly by electronic factors and not steric factors. Thus the reaction has considerable SN1 character. In this case:

    Attack occurs at the C atom that can best accommodate the positive charge.

In base-catalyzed cleavage, the leaving group is a poorer one -- a strongly basic alkoxide oxygen -- and the nucleophile is a good one (e.g. hydroxide, alkoxide).

Bond-breaking and bond-making are more nearly balanced, and reactivity is controlled in the more usual way -- by steric factors. In this case:

                                  Attack occurs at the less hindered carbon.

Epoxides in Biochemistry

Functional group transformations of epoxides rank among the fundamental reactions of organic chemistry, and epoxides are commonplace natural products. The female gypsy moth, for example, attracts the male by emitting an epoxide known as disparlure. On detecting the presence of this pheromone, the male follows the scent to its origin and mates with the female.

The reactivity of epoxides toward nucleophilic ring opening is responsible for one of the biological roles they play. Squalene 2,3-epoxide, for example, is the biological precursor to cholesterol and the steroid hormones, including testosterone, progesterone, estrone, and cortisone.

The pathway from squalene 2,3-epoxide to these compounds is triggered by an epoxide ring opening (see Unit 24: Lipids).