[937-14-4] · C7H5ClO3 · m-Chloroperbenzoic Acid · (MW 172.57)
(electrophilic reagent capable of reacting with many functional groups; delivers oxygen to alkenes, sulfides, selenides, and amines)
Alternate Name: m-CPBA; MCPBA.
Physical Data: mp 92-94 °C.
Solubility: sol CH2Cl2, CHCl3, 1,2-dichloroethane, ethyl acetate, benzene, and ether; slightly sol hexane; insol H2O.
Form Supplied in: white powder, available with purity of 50%, 85%, and 98% (the rest is 3-chlorobenzoic acid and water).
Analysis of Reagent Purity: iodometry.2
Purification: commercial material (purity 85%) is washed with a phosphate buffer of pH 7.5 and dried under reduced pressure to furnish reagent with purity >99%.3
Handling, Storage, and Precautions: pure m-CPBA is shock sensitive and can deflagrate;4 potentially explosive, and care is required while carrying out the reactions and during workup.5 Store in polyethylene containers under refrigeration.
Functional Group Oxidations.
The weak O-O bond of m-CPBA undergoes attack by electron-rich substrates such as simple alkenes, alkenes carrying a variety of functional groups (such as ethers, alcohols, esters, ketones, and amides which are inert to this reagent), some aromatic compounds,6 sulfides, selenides, amines, and N-heterocycles; the result is that an oxygen atom is transferred to the substrate. Ketones and aldehydes undergo oxygen insertion reactions (Baeyer-Villiger oxidation).
Organic peroxy acids (1) readily epoxidize alkenes (eq 1).1b This reaction is syn stereospecific;7 the groups (R1 and R3) which are cis related in the alkene (2) are cis in the epoxidation product (3). The reaction is believed to take place via the transition state (4).8 The reaction rate is high if the group R in (1) is electron withdrawing, and the groups R1, R2, R3, and R4 in (2) are electron releasing.
Epoxidations of alkenes with m-CPBA are usually carried out by mixing the reactants in CH2Cl2 or CHCl3 at 0-25 °C.9 After the reaction is complete the reaction mixture is cooled in an ice bath and the precipitated m-chlorobenzoic acid is removed by filtration. The organic layer is washed with sodium bisulfite solution, NaHCO3 solution, and brine.10 The organic layer is dried and concentrated under reduced pressure. Many epoxides have been purified chromatographically; however, some epoxides decompose during chromatography.11 If distillation (caution: check for peroxides12) is employed to isolate volatile epoxides, a trace of alkali should be added to avoid acid-catalyzed rearrangement.
Alkenes having low reactivity (due to steric or electronic factors) can be epoxidized at high temperatures and by increasing the reaction time.13 The weakly nucleophilic ,-unsaturated ester (5) thus furnishes the epoxide (6) (eq 2).13b When alkenes are epoxidized at 90 °C, best results are obtained if radical inhibitor is added.13a For preparing acid-sensitive epoxides (benzyloxiranes, allyloxiranes) the pH of the reaction medium has to be controlled using NaHCO3 (as solid or as aqueous solution),14 Na2HPO4, or by using the m-CPBA-KF9a reagent.
In the epoxidation of simple alkenes (2) (eq 1), due to the electron-releasing effect of alkyl groups the reactivity rates are tetra- and trisubstituted alkenes > disubstituted alkenes > monosubstituted alkenes.1a High regioselectivity is observed in the epoxidation of diene hydrocarbons (e.g. 7) having double bonds differing in degree of substitution (eq 3).15 Epoxidation takes place selectively at the more electron-rich C-3-C-4 double bond in the dienes (8)16 and (9).17
Diastereoselective Epoxidation of Cyclic Alkenes.
-Facial stereoselectivity (75% anti) is observed in the epoxidation of the allyl ether (10a) since reagent approach from the -face is blocked by the allylic substituent; a higher diastereoselectivity (90% anti epoxidation) is observed when the bulkier O-t-Bu is located on the allylic carbon (eq 4).18 Due to steric and other factors, the norbornene (11) undergoes selective (99%) epoxidation from the exo face.19 In 7,7-dimethylnorbornene (12), approach to the exo face is effectively blocked by the methyl substituent at C-7, and (12) is epoxidized from the unfavored endo face, although much more slowly (1% of the rate of epoxidation of 11).19 The geminal methyl group at C-7 is able to block the approach of the peroxy acid even when the double
In a blatant plug for the Reagent Guide, each Friday I profile a different reagent that is commonly encountered in Org 1/ Org 2.
mCPBA (meta-chloroperoxybenzoic acid) is an extremely useful reagent most frequently encountered in the synthesis of epoxides. You might see mCPBA, MCPBA, or m-CPBA – alternately used. It all boils down to the same thing.
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.
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 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.
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.
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.
P.S. You can read about the chemistry of MCPBA and more than 80 other reagents in undergraduate organic chemistry in the “Organic Chemistry Reagent Guide”, available here as a downloadable PDF.
Tagged as: alkenes, baeyer villiger, epoxidation, epoxides, mCPBA, reagent friday, Reagent guide, reagents, reagents app