m-CPBA (meta-chloroperoxybenzoic acid)

m-Chloroperoxybenzoic Acid (m-CPBA) For The Epoxidation of Alkenes

• m-CPBA (meta-chloroperoxybenzoic acid) is a useful reagent for the formation of epoxides from alkenes (note – often just called, m-chloroperbenzoic acid, without the “oxy”)
• In this reaction, the C-C pi bond is broken, and  two new C-O single bonds are formed on the same face of the alkene pi-bond.  Since both bonds are formed on the same face, this is an example of a syn addition.
• The weak O-O bond in m-CPBA is also broken. The -OH of the peroxyacid is the source of the oxygen in the new epoxide
• Epoxidation of alkenes with m-CPBA is an example of a stereospecific reaction. The configuration of atoms about the C–C bond is always conserved. The reaction proceeds through a concerted transition state.
• Other peroxyacids such as peracetic acid, perbenzoic acid, and trifluoroperacetic acid are also effective reagents for epoxidation of alkenes.
• Alkynes do not undergo reaction with m-CPBA to give epoxides
• m-CPBA is also useful for the Baeyer-Villiger oxidation, a reaction that converts ketones to esters [for more on this, see post – The Baeyer-Villiger Reaction]

Table of Contents

1. 1. Epoxidation of Alkenes With Peroxyacids
   2. Epoxidation of Alkenes Is Stereospecific
   3. Mechanism for the Epoxidation of Alkenes
   4. Which Alkene Will React?
   5. Stereoselectivity
   6. Other Epoxidation Reagents
   7. Sharpless Asymmetric Epoxidation
   8. Notes
   9. Quiz Yourself!
   10. (Advanced) References and Further Reading

1. Epoxidation of Alkenes With Peroxyacids

When alkenes are treated with peroxyacids such as meta-chloroperoxybenzoic acid (m-CPBA), two new C-O bonds are formed and a C-C pi bond is broken, resulting in the formation of an epoxide. (An O–O bond from m-CPBA is also broken, which is the source of the oxygen in the epoxide. The byproduct is m-chlorobenzoic acid).

Epoxides, also known as oxiranes, are 3-membered cyclic ethers. Since the inner bond angles of epoxides (approximately 60°) deviate significantly from the preferred tetrahedral geometry around carbon (109.5°) , they possess considerable ring strain (about 13 kcal/mol) and undergo a large number of useful ring-opening reactions with nucleophiles. (For more on the reactions of epoxides, see Epoxides – the Outlier of the Ether Family]

Epoxidation of alkenes with peroxyacids such as m-CPBA always occurs in such a way that both C-O bonds are formed on the same face of the alkene, an outcome known as “syn addition”.

You can tell that addition is syn here because the new C-O bonds are both drawn as “wedges” (pointing out of the page) or “dashes” (pointing into the page).

In this case both of these products are identical, since rotating the molecule 180° results in the same product (see below)

via GIPHY (Look at how unhappy those plastic pieces are – the model kit really helps you visualize the ring strain :- ) )

In many other cases this will result in the formation of a pair of enantiomers or diasteromers, depending on the structure of the starting alkene.

Epoxidation of alkenes with peroxyacids never results in anti addition.

It is incorrect to draw the product of this epoxidation reaction as having one “wedge” C-O and one “dash” C-O, since this would represent anti addition.

(BTW if you try to make a model, you will see that this outcome would also be impossibly strained)

2. Epoxidation of Alkenes Is Stereospecific

In epoxidation reactions, the configuration of atoms about the alkene is always conserved.

For example, the trans alkene below gives only the trans product (as an equal mixture of enantiomers). Note that in product A, the trans arrangement of C–H bonds about the C–C bond has been conserved.

The product B where the two C-H bonds are cis to the C-C bond is not formed. (Note that this product B would be the diastereomer of product A).

Likewise, the cis alkene gives only product B. (Product A, diastereomers of product B, are not formed.)

Since the starting trans and cis alkenes differ only in their configuration but yield products which are stereoisomers, epoxidation of alkenes is therefore an example of a stereospecific reaction. [see IUPAC for the definition, also see article: Stereoselective and Stereospecific Reactions]

Click to Flip

3. The Mechanism of Epoxidation of Alkenes With m-CPBA

Now that we’ve identified the bonds that form and break, and the expected stereochemistry for this reaction, we can start to ask ourselves how this reaction actually works.

First of all: which oxygen from m-CPBA is transferred to give the epoxide?

Isotopic labelling studies can verify that the oxygen of the epoxide comes from the OH of the peroxyacid, not the interior O connected to the C=O.

One driving force for the reaction is breakage of the relatively weak O–O and C-C pi bonds (bond dissocation energies of about 45 kcal/mol and 60 kcal/mol, respectively) in exchange for two relatively strong C-O sigma bonds (about 90 kcal/mol).

The transition state that has been proposed for the reaction of m-CPBA (and other peroxyacids) with alkenes has become known as the “butterfly mechanism”, owing to the four(!) partial bonds around the central oxygen that give the appearance of a large-winged insect.

This reaction gets my vote for the busiest one-step arrow-pushing mechanism in all of introductory organic chemistry:

Let’s break down everything that happens here in this one (!) step:

• The C–C pi bond breaks
• Two new C–O single bonds form
• The (weak) O–OH bond breaks
• Meanwhile, the resulting carboxylic acid is transposed: a new C–O pi bond forms, while the existing C-O pi bond acts as a base to remove a proton from the terminal oxygen.

This “butterfly” mechanism accounts for the following experimental observations:

• The reaction is first-order in both peroxyacid and alkene (second order overall)
• The rate of reaction is not sensitive to the polarity of the solvent (making a charged carbocation intermediate unlikely) [Note 1]

It also accounts for the stereospecificity of the reaction. We would not expect a reaction that proceeds through a carbocation intermediate to be stereospecific, for example.  (The reaction of HCl with alkenes is not stereospecific, for example)

Two additional facts are worth noting.

• Electron-rich alkenes react more quickly than electron poor alkenes [Ref], and
• adding electron-withdrawing groups to the R group of the peroxyacid make it more reactive. (The added chlorine on the 3-position of the benzene ring makes it more electron-withdrawing and therefore more reactive, relative to plain-ol’ peroxybenzoic acid). 

4. Which Alkene Will React?

Let’s imagine we have a molecule containing multiple C-C pi bonds that is treated with m-CPBA.

Is it possible to get epoxidation to happen at just one alkene pi-bond, or do we just end up with a mixture of products?

What is observed is that the most electron-rich alkene undergoes epoxidation first, with remarkably good selectivity.

“Most electron-rich” generally means the alkene which has the most carbon atoms directly attached to the alkene (i.e. “most substituted”) so long as they are not electron-withdrawing groups.

For instance, in the alkene above, it’s the trisubstituted alkene preferentially undergoes epoxidation while the mono-substituted alkene is untouched.

This might seem counter-intuitive since we might expect that a more substituted alkene is more sterically hindered, but in practice the rate of reaction is more sensitive to electronic effects (i.e. electron-rich vs. electron-poor) than steric effects. [Note 2] [Ref]

See if you can apply this concept in the question below:

Click to Flip

5. Stereoselectivity

When epoxidation is performed on an alkene containing pre-existing chiral centers, then there is the potential for the formation of stereoisomers. That’s because the two faces of the alkene will not be equivalent steric environments, as seen from the perspective of electrophile (such as m-CPBA).

A particularly striking example is the bicyclic alkene below. When it is treated with m-CPBA, a 99:1 mixture of products (diastereomers)  is formed. The reason for the high selectivity is that the electrophile (m-CPBA) only encounters a single CH₂ group in its approach to the top face (favored), whereas it encounters a two-carbon bridge in is approach on the bottom face (disfavored).

In this case, the result is a 99:1 ratio of products favoring attack on the least hindered face of the alkene.

There is a more systematic method for naming faces of alkenes, (known as Re and Si ) which we will not get into at present. 

6. Other Epoxidation Reagents

Other peroxyacids have been used for epoxidation reactions, such as peroxyacetic acid, peroxybenzoic acid, and trifluoroperoxyacetic acid.

Just as making the alkene more electron-rich increases the rate of reaction, it has also been observed that adding electron-withdrawing reagents to the electrophile (peroxyacid) increases the rate of reaction.

The epoxidation of alkenes with peroxyacids has been known since 1909, but it was only in the 1960s that m-CPBA started gaining widespread use, which greatly improved the scope of epoxidation reactions. [Note 3]

Furthermore, although they aren’t often covered in introductory courses, there are other ways of epoxidizing alkenes that don’t involve peroxyacids. Examples include metals such as vanadium, titanium, manganese and others in the presence of peroxides (or hydroperoxides), or the use of reagents such as dimethyldioxirane (DMDO).

7. Sharpless Asymmetric Epoxidation

Enantioselective epoxidation of alkenes is also a known process.

In an enantioselective reaction, one starts with an achiral molecule and adds a chiral reagent that selectively attacks one face of the starting material over the other, resulting in a mixture of products which is enriched in on enantiomer over another. (One can’t just use any chiral reagent – there’s a lot of trial and error involved in getting the right recipe) [Note]

One prominent method for the enantioselective epoxidation of alkenes was developed by K. Barry Sharpless (Scripps) and has become known as the Sharpless epoxidation.

The Sharpless epoxidation involves treating an allylic alcohol with a witches’ brew of titanium isopropoxide [Ti(Oi-Pr)₄)] t-butylhydroperoxide (the oxidant) and, depending on which enantiomer is desired, either (S,S) or (R, R) diethyl tartrate (or di-isopropyl tartrate, in some cases)

Here is a simple example.

The reaction is not enantioselective without the OH group on the carbon adjacent to the alkene. (This class of molecules is known as “allylic alcohols”).  The hydroxyl group is required to coordinate to the titanium and direct the epoxidation.

For much more on the Sharpless epoxidation, I highly recommend these notes (Chemistry 115, Harvard University, Prof. Andrew G. Myers).

Notes

For this article, Encyclopedia of Reagents for Organic Synthesis was very useful [See on archive.org] , as was March’s Advanced Organic Chemistry and Prof Andrew Myers’ Chem 115 Notes (Harvard).

Note 1.  A typical solvent for epoxidation with m-CPBA is the relatively non-polar solvent dichloromethane. Interestingly, the rate of epoxidation is much slower in hydrogen-bonding solvents, as these tend to disrupt the internal hydrogen bonding of the “butterfly” transition state. [Ref]

Note 2.  This reminds me of an old joke among organic chemistry graduate students: if you’re asked at a group meeting to explain why a particular reaction happens (or doesn’t happen), the stock answer is, “a combination of electronics and sterics”. Covers all the bases!

Note 3.  The reactivity of m-CPBA is highly superior to that of peroxybenzoic acid, but only became widely available after 1963. For a comparison of the scope of peroxybenzoic acid and m-CPBA, compare [Ref] and [Ref] – m-CPBA gives cleaner and faster reactions, with greater scope. It is also a nicely crystalline white solid. Commercially available m-CPBA consists of about 80% m-CPBA with the remainder being m-chlorobenzoic acid. It can be purified further by treating with a buffer, but great care should be taken with highly purified m-CPBA due to its potentially explosive properties.

Note 4. To give an idea of the trial and error involved in the development of this reaction, see Sharpless’ Nobel Lecture. (the first one, in 2001, not the second one from 2022). The two full papers [here] and [here] on determining the mechanism of the reaction are classic examples of meticulous, systematic experimental work.

Quiz Yourself!

Here’s a quiz on identifying the relationship between products of epoxidation reactions. (Note – for more examples of these types of quizzes, see this post on “What’s A Racemic Mixture“.)

Click to Flip

(Advanced) References and Further Reading

(Advanced) References and Further Reading

1. Oxydation ungesättigter Verbindungen mittels organischer Superoxyde
   Nikolaus Prileschaev
   Chem. Ber. 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.
2. The oxidation of olefins with perbenzoic acids. A kinetic study
   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.
3. m-CHLOROPERBENZOIC ACID
   Richard N. McDonald, Richard N. Steppel, and James E. Dorsey.
   Org. Synth. 1970, 50, 15.
   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).
4. Epoxidations with m-Chloroperbenzoic Acid
   Nelson N. Schwartz and John H. Blumbergs.
   J. Org. Chem. 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.
5. Record of chemical progress
   Bartlett, P. D.
   Chem. Prog. 1950, 11, 47
   [Link]
   This is the publication in which Prof. P. D. Bartlett describes the ‘butterfly mechanism’ for m-CPBA epoxidation.
6. MCPBA Epoxidation of Alkenes: Reinvestigation of Correlation between Rate and Ionization Potential
   Cheal Kim, Teddy G. Traylor, and Charles L. Perrin.
   J. Am. Chem. Soc. 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.
7. Experimental Geometry of the Epoxidation Transition State
   Daniel A. Singleton, Steven R. Merrigan, Jian Liu, and K. N. Houk.
   J. Am. Chem. Soc. 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.
8. The mechanism of epoxidation of olefins by peracids
   V. G. Dryuk.
   Tetrahedron. Volume 32, Issue 23, 1976, 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.
9. The Bond Dissociation Energy of Peroxides Revisited
   https://pubs.acs.org/action/showCitFormats?doi=10.1021/acs.jpca.0c02859&ref=pdf
10. The first practical method for asymmetric epoxidation
    Tsutomu Katsuki and K. Barry Sharpless
    Journal of the American Chemical Society 1980 102 (18), 5974-5976
    DOI: 10.1021/ja00538a077
    Katsuki and Sharpless’ first report from 1980 on the asymmetric epoxidation reaction of allylic alcohols.