Reagent Friday: m-CPBA (meta-chloroperoxybenzoic acid)
Last updated: January 29th, 2020 |
In a blatant plug for the Reagent Guide, each Friday I profile a different reagent that is commonly encountered in Org 1/ Org 2.
Notice how the molecule looks like a carboxylic acid, but has an extra O. That’s what’s called a “per-acid” – it should be reminiscent of the difference between hydrogen per-oxide (HOOH) and hydrogen oxide (H2O). Note that the oxygen-oxygen bond is quite weak (about 33 kcal/mol or 138 kJ/mol). As we shall see, this is what leads to the high reactivity of these compounds.
Oxidation Of Alkenes With mCPBA
mCPBA forms epoxides when added to alkenes. One of the key features of this reaction is that the stereochemistry is always retained. That is, a cis alkene will give the cis-epoxide, and a trans alkene will give a trans epoxide. This is a prime example of a stereoselective reaction.
The Concerted Mechanism For Epoxidation Of Alkenes With mCPBA
The reaction itself happens through a “concerted” transition state. That is, the bond between the oxygen and the alkene is being formed at the same time that the O-O bond is breaking and the proton is being transferred from the OH to the carbonyl oxygen. Those little dotted lines represent partial bonds.
The epoxides that are formed are useful in all kinds of ways. Mostly, they are good electrophiles that will react with nucleophiles such as Grignard or organolithium reagents, hydroxide or alkoxide ions, or (in the presence of acid) water.
The Baeyer-Villiger Oxidation Of Ketones To Esters
Another useful reaction of mCPBA – commonly encountered in Org 2 – is the Baeyer-Villiger reaction. This is a rare example of a reaction that results in the oxidation of a ketone – remember that chromic acid leaves ketones alone, for instance. mCPBA can also oxidize aldehydes.
Mechanism For The Baeyer-Villiger Oxidation Of Ketones With m-CPBA
The first step of the Baeyer-Villiger reaction is a 1,2 addition of the per-acid oxygen to the carbonyl of the ketone. Then there’s a proton transfer. [Note: when the pros do this reaction, they often add a mild base like sodium bicarbonate, which will speed up the reaction by making the conjugate base of mCPBA – a better nucleophile]. Now comes the fun part. The lone pair on the oxygen then re-forms the C=O bond, which then leads to a 1,2-shift of a carbon bond to the oxygen, breaking the (weak) oxygen-oxygen bond and forming an ester in the process. (Remember – if you ever have to sketch this mechanism out, draw the ugly version first).
How do you know which bond will migrate? Great question. Migrating group ability corresponds – somewhat – with carbocation stability. Suffice it to say that H is the best migrating group, tertiary alkyls are next, and methyl groups are the worst. Aryl groups (like this benzene group in the example) are at the lower middle range of the scale.
Why is this reaction useful? Well, let’s say you have a ketone on an aromatic ring (a meta director) and you want to make the ortho or para product. If you do a Baeyer-Villiger with mCPBA, you will transform it into an ester with the oxygen on the ring (an ortho para director). Now you can add your electrophile. This trick comes in handy.
For the record, other peracids like peroxybenzoic acid or peroxyacetic acid will do the same chemistry as mCPBA. mCPBA tends to get a lot of use due to the fact that it is more reactive than peroxybenzoic acid, and also a nicely crystalline white solid.
(Advanced) References and Further Reading
- 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.
- 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.
- m-CHLOROPERBENZOIC ACID
Richard N. McDonald, Richard N. Steppel, and James E. Dorsey. 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).
- 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.
- Record of chemical progress
Bartlett, P. D. Chem. Prog. 1950, 11, 47
This is the publication in which Prof. P. D. Bartlett describes the ‘butterfly mechanism’ for m-CPBA epoxidation.
- 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.
- 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.
- 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.