Epoxides – The Outlier Of The Ether Family

Properties and Synthesis of Epoxides 

• Epoxides (oxiranes) are cyclic ethers that have unusually high reactivity due to ring strain (about 25 kcal/mol).
• The 3-membered ring of epoxides can be opened under both acidic and basic conditions.
• Epoxides can be synthesized from alkenes via epoxidation with a peroxyacid like m-CPBA, or from halohydrins via treatment with base.

Table of Contents

1. Cleavage  of Ethers Generally Requires Very  Harsh Conditions
2. Epoxides (“Oxiranes”) Are An Unusually Reactive Type of Cyclic Ether
3. Epoxides React With Aqueous Acid Under Mild Conditions To Form Diols
4. Unlike Most Ethers, Epoxides Can Be Easily  Cleaved With Aqueous Base
5. Synthesis of Epoxides (1): Reaction of Alkenes With A Peroxyacid
6. Synthesis of Epoxides (2): Treating Halohydrins With Base
7. Opening Of Epoxides Gives Different Products  Depending  On Whether Acid Or Base Is Used
8. Notes
9. (Advanced) References and Further Reading

1. Cleavage of Ethers Generally Requires Very Harsh Conditions

In the last post, I wrote that ethers were quite possibly the most boring functional group of all, at least from the perspective of reactivity. This got some friendly flak from an inorganic chemist in the crowd, but for our purposes, it’s true. We only cover one reaction: how to cleave ethers with strong acid.
To review, here’s what this reaction looks like for several different ethers. Since an “ether” is a functional group with an oxygen connected to two carbons, this also includes cyclic cases such as the five membered and three membered cyclic ethers below.

In this reaction, we protonate the ether oxygen with strong acid [making a good leaving group] and one of the adjacent carbons is then attacked by a nucleophile [I- in this case] leading to the rupture of the C-O bond and formation of the alcohol and alkyl iodide shown above.

Opening up a cyclic molecule is akin to taking off a belt: by opening up the “buckle” [i.e. breaking the C-O bond] we go from a “loop” back to a “strip”. It is the same with cyclic molecules – see how the second and third examples open to give linear products.

By the way, that first example is the answer to the quiz at the bottom of the last post. The second example shows the cyclic ether tetrahydrofuran (THF), which you’ve probably seen in other contexts – as an organic solvent, for instance. The third example shows a class of molecules you’ve likely seen before but might not have thought of as an ether – the three-membered cyclic ethers we call “epoxides” [or sometimes, “oxiranes“].

2. Epoxides (“Oxiranes”) Are An Unusually Reactive Type of Cyclic Ether

If you think of ethers as a generally staid, stable, and placid family of functional groups, epoxides are definitely the outlier.

What makes epoxides so unusual – and interesting?

The interior bond angles of epoxides are about 60°. Contrast that with the “ideal” bond angle of 109.5° for tetrahedral carbon, and you’ll appreciate that like cyclopropane discussed earlier, they possess considerable ring strain.

This ring strain – about 25 kcal/mol [Ref]- has the effect of making them”spring-loaded” if you will, toward opening.

[It’s important to keep one thing in mind when drawing epoxides, especially with respect to their position on rings. The two C-O bonds must always be on the same “face” of the ring [i.e. making a “cis” ring junction]. The “trans” ring junction version is too strained to exist]

Let’s look at some examples of how epoxides are more reactive than “regular” ethers.

3. Epoxides React With Aqueous Acid Under Mild Conditions To Form Diols

First of all, they react with acid under much milder conditions than, say, diethyl ether. For example, treating an epoxide with aqueous acid [H₃O+] will open an epoxide to provide a 1,2-diol [often called a “vicinal diol” or a “glycol”]. Under the same conditions that open the epoxide, diethyl ether is inert [as are most ethers].

[We’ll explore this reaction of epoxides in more detail in subsequent posts].

4. Unlike Most Ethers, Epoxides Can Be Easily  Cleaved With Aqueous Base

Secondly: unlike the vast majority of ethers, epoxides can also be cleaved with base. For example, treatment of an epoxide such as ethylene oxide with sodium hydroxide in water similarly leads to formation of a vicinal diol [this is “ethylene glycol“, by the way, a common component of antifreeze].

Other nucleophiles besides hydroxide ion can be used to open ethers (see post: Opening of Epoxides With Base)

The key point to absorb here is that epoxides are not typical ethers, and thus deserve their own discussion. 

Let’s back up a bit.

5. Synthesis of Epoxides (1): Reaction of Alkenes With A Peroxyacid

I mentioned that you’d likely seen epoxides before, likely when you covered the reaction of alkenes. There’s two important ways to make epoxides from alkenes, one “direct” and one “indirect”. Let’s review the first method.

Treating an alkene with a “peroxyacid” (that’s a carboxylic acid containing an extra oxygen) leads to direct formation of an epoxide. A popular peroxyacid for this purpose is m-CPBA [m-chloroperoxybenzoic acid], although other peroxyacids of the general form RCO₃H also find use. We talked about this reaction in more detail here.  (See post: Reactions of Alkenes – the Concerted Pathway)

6. Synthesis of Epoxides (2): Treating Halohydrins With Base

There’s a second way to make epoxides via a two-step process that I don’t believe we’ve covered here before.  Starting with an alkene, if one adds a halogen (such as Br₂ or Cl₂) and water as solvent, we make a species known as a halohydrin. Treatment of a halohydrin with strong base (such as NaH or NaOH) leads to deprotonation of the OH to give O- , which then displaces the adjacent halide via S_N2 reaction to provide the resulting epoxide. [why deprotonation and not S_N2? see Note 1]

Note that stereochemistry is important here! S_N2 reactions proceed via a backside attack, (See post: The SN2 Mechanism) leading to inversion of configuration. If the halohydrin is “locked” in position (as part of a ring, for example) and the alkoxide [O- ] cannot approach the backside of the C-Br bond, then the S_N2 cannot occur and therefore an epoxide will not be formed. Instructors love to ask questions like this, so be alert!

7. Opening Of Epoxides Gives Different Products  Depending  On Whether Acid Or Base Is Used

This post has given us a little taste of the properties, reactions, and synthesis of epoxides, but there are many more details to explore here. For example, if you are very observant, you might have noticed an odd thing about the reactions of that cyclohexane epoxide from the acid and base slides: it gives a different product depending on whether H₃O+ or NaOH is added!

This isn’t a typo! This represents the actual pattern of reactivity of this epoxide. Isn’t it strange that NaOH and H₃O+ should lead to different products. Why might that be?

One hint: this is a consequence of the fact that these reactions go through different mechanisms. Mechanisms that – believe it or not – we have seen before, in one form or another. However, this dichotomy of mechanism is a prime source of confusion for students on this topic, and again, one that tends to be heavily tested on exams.

We’ll start to delve into this mystery in the next post – as well as explore the reactions of epoxides in greater detail.

Next Post – Opening Of Epoxides With Acid

Notes

Note 1. By the way: you might ask – why doesn’t NaOH just do a backside attack on the C-Br bond in the first example? The answer is that acid-base reactions tend to be fast relative to substitution reactions, because there is very little atomic reorganization required. Secondly, once the alcohol has been deprotonated, the intramolecular S_N2 reaction [forming the epoxide] is faster than the intermolecular S_N2 forming a new alcohol, because the proximity of the O- to the C-Br gives it a higher “effective concentration”. ]

(Advanced) References and Further Reading

Epoxide formation from halohydrins:

This reaction can be considered as an internal Williamson Ether Synthesis.

1. CYCLOHEXENE OXIDE
   A. E. Osterberg
   Org. Synth. 1925, 5, 35
   DOI: 10.15227/orgsyn.005.0035
   Simple, straightforward Organic Syntheses prep of cyclohexene oxide from the chlorohydrin.
2. Kinetics of formation of substituted styrene oxides by reaction of 2-aryl- and 1-aryl-2-halogenoethanols with aqueous alkali
   Anthony C. Knipe
   J. Chem. Soc. Perkin Trans. 2 1973, 589-595
   DOI: 10.1039/P29730000589
   This paper studies the kinetics of styrene oxide formation using a Hammett plot, a classic tool of physical organic chemistry.
3. Stereochemical Aspects of the Synthesis of 1,2‐Epoxides
   Giancarlo Berti
   Topics in Stereochemistry 1973, 93
   DOI:1002/9780470147160.ch2
   See page 187 in this review for a detailed discussion of the formation of epoxides from halohydrins.
4. Neighboring group effects in the regioselective cyclization of vicinal trans-1,2-bromohydrins to epoxides
   Fengrui Lang, Darren J. Kassab, Bruce Ganem
   Tetrahedron Lett. 1998, 39 (33), 5903-5906
   DOI: 10.1016/S0040-4039(98)01243-X
   The course of this intramolecular epoxide formation can also be influenced by neighboring group effects.
5. Diastereo- and enantioselective synthesis of α,β-epoxyketones using aqueous NaOCl in conjunction with dihydrocinchonidine derived phase-transfer catalysis at room temperature. Scope and limitations
   Barry Lygo, Stuart D. Gardiner, Michael C. McLeod, and Daniel C. M. To
   Org.  Biomol. Chem. 2007, 5, 2283-2290
   DOI: 10.1039/B706546A
   Enantioselective epoxide-forming reactions are known, using chiral additives (e.g. dihydrocinchonidines).Epoxidation of alkenes with m-CPBA:
6. Oxydation ungesättigter Verbindungen mittels organischer Superoxyde
   Nikolaus Prileschajew
   Chemische Berichte 1909 42, 4811
   DOI: 10.1002/cber.190904204100
   This reaction (epoxidations of alkenes with a peracid) is also known as the Prizelhaev reaction after the author.
7. The oxidation of olefins with perbenzoic acids. A kinetic study
   B. M. Lynch and K. H. Pausacker
   J. Chem. Soc., 1955, 1525-1531
   DOI: 10.1039/JR9550001525
   One of the earliest papers on epoxidation with m-CPBA, comparing its reactivity with other substituted peracids. As expected, the reactivity of peroxyacids is increased by electron-withdrawing groups.
8. m-CHLOROPERBENZOIC ACID
   Richard N. McDonald, Richard N. Steppel, and James E. Dorsey
   Org Synth. Vol. 50, p.15 (1970)
   DOI: 10.15227/orgsyn.050.0015
   A reliable preparation for m-CPBA (which is commercially available) in Organic Syntheses. As this procedure shows, m-CPBA is not prepared as a pure compound (it is a mixture of the peracid and acid, and commercial samples may contain residual water for stability).
9. Epoxidations with m-Chloroperbenzoic Acid
   Nelson N. Schwartz and John H. Blumbergs
   The Journal of Organic Chemistry 1964 29 (7), 1976-1979
   DOI: 1021/jo01030a078
   This paper describes mechanistic studies of m-CPBA oxidation that demonstrate that ionic intermediates are not involved in the reaction, and that the rate is insensitive to solvent polarity.
10. Bartlett, P. D.
    Rec. Chem. Prog. 1950, 11, 47
    This is the publication in which Prof. P. D. Bartlett describes the ‘butterfly mechanism’ for m-CPBA epoxidation.
11. MCPBA Epoxidation of Alkenes:  Reinvestigation of Correlation between Rate and Ionization Potential
    Cheal Kim, Teddy G. Traylor, and Charles L. Perrin
    Journal of the American Chemical Society 1998 120 (37), 9513-9516
    DOI:1021/ja981531e
    An interesting paper that describes the development of a kinetic method for measuring the rate of epoxidation of various alkenes with m-CPBA.
12. Experimental Geometry of the Epoxidation Transition State
    Daniel A. Singleton, Steven R. Merrigan, Jian Liu, and K. N. Houk
    Journal of the American Chemical Society 1997 119 (14), 3385-3386
    DOI:1021/ja963656u
    Combined experimental and theoretical studies of the epoxidation transition state, showing that both C-O bond forming events are nearly synchronous.
13. The mechanism of epoxidation of olefins by peracids
    V. G. Dryuk
    Tetrahedron Volume 32, Issue 23, 1976, Pages 2855-2866
    DOI: 10.1016/0040-4020(76)80137-8
    An account of the author’s work on kinetic studies of the epoxidation of olefins with peracids in order to determine the exact mechanism.
14. Thermochemical Studies of Epoxides and Related Compounds
    Kathleen M. Morgan, Jamie A. Ellis, Joseph Lee, Ashley Fulton, Shavonda L. Wilson, Patrick S. Dupart, and Rosanna Dastoori
    The Journal of Organic Chemistry 2013, 78 (9), 4303-4311
    DOI: 1021/jo4002867
    Table 7 in this paper contains strain energies of cyclopropane, epoxides, aziridines, thiiranes, and the phosphorous analog (which is purely theoretical). Table 8 contains strain energies of epoxides. These values are obtained through computational methods, and are compared with experimentally derived values where possible. Oxirane has a strain energy of 27.3 kcal/mol, which is reduced with alkyl substitution.

 Note – an earlier version of this article quoted a ring strain for epoxides of about 13 kcal/mol. This is in error.