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Alcohols, Epoxides and Ethers

By James Ashenhurst

Epoxides – The Outlier Of The Ether Family

Last updated: September 16th, 2020 |

Properties and Synthesis of Epoxides

 In this post we discuss a special class of ethers that has unusually high reactivity due to their ring strain – epoxides. Here’s a summary of what we’ll talk about here:  

summary of epoxides much more reactive than normal ethers due to ring strain synthesis through halohydrin formation

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.

hi strong acid cleaves ethers such as anisole tetrahydrofurane and especially ethylene oxide epoxide

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.

awkward family photos outlier of the family epoxides

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 13 kcal/mol – has the effect of making them”spring-loaded” if you will, toward opening.

epoxides oxiranes are unusually reactive type of cyclic ether ring strain about 13 kcal mol only have cis ring junctions

[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].

epoxides cleaved with acid under much milder conditions than normal ethers like aqueous acid h3o gives trans diols

[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].

unlike most ethers epoxides can be easily cleaved with strong base like naoh or naoet

Other nucleophiles besides hydroxide ion can be used to open ethers – we’ll talk about that soon.

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.

epoxides can be synthesized through treatment of alkenes with peroxyacids such as mcpba gives syn product

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 SN2 reaction to provide the resulting epoxide. [why deprotonation and not SN2? see note]

second way to synthesize epoxides is through formation of halohydrins from ethers and treat with base giving epoxides has to be trans

Note that stereochemistry is important here! SN2 reactions proceed via a backside attack, 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 SN2 cannot occur and therefore an epoxide will not be formed. Instructors love to ask questions like this, so be alert!

for halohydrins to give epoxides oh and br have to be on opposite sides of the ring otherwise backside attack not possible

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!

epoxide opening is condition dependent if you use basic or acidic conditions get different results basic is sn2 like acidic is sn1 like

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

[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 SN2 reaction [forming the epoxide] is faster than the intermolecular SN2 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.

 

Comments

Comment section

8 thoughts on “Epoxides – The Outlier Of The Ether Family

  1. I think you made a mistake when talking about the preparation of epoxides.

    You say:

    “Treating an epoxide with a “peroxyacid” (that’s a carboxylic acid containing an extra oxygen) leads to direct formation of an epoxide.”

    when it should be:

    “Treating an alkene with a “peroxyacid” (that’s a carboxylic acid containing an extra oxygen) leads to direct formation of an epoxide.”

      1. Hi my genius namesake! Just a small note, you didn’t fix that typo (“epoxide” instead of “alkene”) in the Epoxide Synthesis (1) diagram.

  2. Didn’t you say that for acid-base reactions to occur, we need a pKa difference of about 10?
    In the first example, the base is OH- and the acid is ROH… So what’s going on?

    1. For acid-base reactions to be *irreversible* there needs to be a pKa difference of 10.

      For ROH and NaOH you’ll have an equilibrium where the two species are about equal in concentration. However once you form RO- it’s a fast reaction to form the epoxide, and that spits out Br- . Eventually you’ll end up with the final product.

  3. Can you please make a page explaining stereochemistry of epoxidation of aliphatic alkenes. I am confused is there syn addition or anti addition in epoxidation. What happens in the cis and trans configuration?

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