The Baeyer-Villiger oxidation: Criegee intermediate, migratory aptitude, and lactone regiochemistry

Intuition Beginner

The Baeyer-Villiger oxidation turns a ketone into an ester (or a cyclic ketone into a lactone) by inserting a single oxygen atom next to the carbonyl. The reagent is a peracid -- usually $m$-chloroperoxybenzoic acid ($m$CPBA), which carries an extra oxygen on its carboxyl group as an $-$O$-$OH peroxide linkage. When the peracid meets the carbonyl, one of the peracid's oxygens transfers to the substrate: it inserts between the carbonyl carbon and one of its neighbours. The bond that migrates -- sliding from carbon to the new oxygen -- determines which side of the carbonyl receives the insert.

For a cyclic ketone this insertion expands the ring by one atom. Cyclohexanone (six carbons in a ring with one carbonyl) becomes $\epsilon$-caprolactone (a seven-membered ring containing one oxygen atom, the lactone). Caprolactone is the monomer polymerised to make polycaprolactone, a biodegradable plastic, and is converted commercially into caprolactam for Nylon-6. For an acyclic ketone like acetophenone (${\text{C}}_6{\text{H}}_5{\text{-CO-CH}}_3$) the phenyl group migrates preferentially over the methyl, giving phenyl acetate (${\text{C}}_6{\text{H}}_5{\text{-O-CO-CH}}_3$) -- an aryl ester, not a methyl benzoate.

The rule that decides which group migrates is called migratory aptitude, and it tracks how well each group stabilises positive charge in the moment of bond-shifting. This is the central reactivity pattern of the Baeyer-Villiger oxidation: regioselective oxygen insertion governed by which substituent can best slide to the new oxygen as the peracid's O$-$O bond cleaves.

Visual Beginner

Picture cyclohexanone as a six-membered ring with the carbonyl carbon at the top. The peracid ($m$CPBA) approaches from above the carbonyl. The terminal $-$OH of the peracid's $-$CO$-$O$-$OH group attacks the carbonyl carbon, opening the C=O pi bond and forming the tetrahedral Criegee intermediate with the peroxy ester substituent dangling off the carbon.

Next, in a single concerted step, one of the two carbon-adjacent bonds slides over to the neighbouring oxygen. As this bond migrates, the weak O$-$O bond breaks and the carboxylate ($m$-chlorobenzoate) departs as the leaving group. The result is a seven-membered ring with one oxygen atom in the chain -- the lactone $\epsilon$-caprolactone.

The picture shows three states: the carbonyl with peracid approaching, the tetrahedral Criegee intermediate with the O$-$O bond in place, and the expanded-ring lactone product with the carboxylate leaving group departing.

Worked example Beginner

Cyclohexanone + $m$CPBA gives $\epsilon$-caprolactone. Show the steps.

Reagents: cyclohexanone (1.0 equiv), $m$CPBA (1.2 equiv) in dichloromethane, with ${\text{NaHCO}}_3$ buffer to neutralise the $m$-chlorobenzoic acid byproduct. Reaction runs at 0 to 25 ${}^{\circ }$C for several hours.

Step 1. The peracid's terminal $-$OH attacks the carbonyl carbon of cyclohexanone. The C=O pi bond opens. The carbonyl oxygen becomes $-$O${}^{-}$ (then is protonated to $-$OH). The tetrahedral Criegee intermediate is formed: the former carbonyl carbon now bears $-$OH, $-$O$-$O$-$CO$-$Ar (the peroxy ester), and two ring carbons.

Step 2. One of the two ring C$-$C bonds adjacent to the carbon migrates to the neighbouring oxygen. Because cyclohexanone is symmetric, both sides are equivalent -- either migration gives the same product. As the C$-$C bond slides over, the weak O$-$O bond breaks, and $m$-chlorobenzoate (${\text{ArCO}}_2^{-}$) departs as the leaving group.

Step 3. The product is $\epsilon$-caprolactone: a seven-membered ring with one oxygen and one carbonyl, ${\text{-(CH}}_2{\text{)}}_5\text{-CO-O-}$. The oxygen of the original carbonyl is now part of the ester linkage; the inserted oxygen came from the peracid.

What this tells us: the Baeyer-Villiger oxidation inserts exactly one oxygen atom adjacent to a carbonyl, expanding cyclic ketones by one ring atom and converting acyclic ketones to esters. Regioselectivity is governed by migratory aptitude.

Check your understanding Beginner

Formal definition Intermediate+

The Baeyer-Villiger oxidation is the peracid oxidation of a ketone or aldehyde to an ester or carboxylic acid, proceeding through the tetrahedral Criegee intermediate and a concerted 1,2-migration with concomitant O$-$O bond cleavage.

Mechanism. For a ketone ${\text{R}}_1{\text{-CO-R}}_2$ and a peracid ${\text{R}}_3{\text{CO}}_3\text{H}$ (typically $m$CPBA, ${\text{R}}_3=3{\text{-Cl-C}}_6{\text{H}}_4$):

$${\text{R}}_1{\text{-CO-R}}_2+{\text{R}}_3{\text{CO}}_3\text{H}⟶{\text{R}}_1{\text{-CO-O-R}}_2\text{or}{\text{R}}_2{\text{-CO-O-R}}_1$$

The mechanism has three stages.

Stage 1. Nucleophilic addition of the peracid's terminal hydroxyl oxygen to the carbonyl carbon. The C=O pi bond breaks, giving a tetrahedral alkoxide that is protonated on the former carbonyl oxygen (acid catalysis accelerates the addition by activating the carbonyl toward nucleophilic attack). The intermediate is the Criegee intermediate:

$${\text{R}}_1{\text{R}}_2{\text{C(OH)(O-O-CO-R}}_3\text{)}$$

This species is tetrahedral at the former carbonyl carbon, bears a hydroxyl group (the former carbonyl oxygen), and carries the peroxy ester linkage $-$O$-$O$-$CO$-$R${}_3$ that will become the leaving group.

Stage 2. Concerted 1,2-rearrangement. One of the two groups on the former carbonyl carbon (${\text{R}}_1$ or ${\text{R}}_2$) migrates to the adjacent peroxy oxygen as the O$-$O bond cleaves heterolytically. The migrating group retains its stereochemical configuration. The leaving group departs as ${\text{R}}_3{\text{CO}}_2^{-}$ (a carboxylate). The product is the protonated ester:

$${\text{R}}_1{\text{R}}_2{\text{C(OH)(O-O-CO-R}}_3\text{)}⟶{\text{R}}_{\text{migr}}{\text{-O-CO-R}}_{\text{nonmigr}}+{\text{R}}_3{\text{CO}}_2^{-}{\text{H}}^{+}$$

The migrating group ${\text{R}}_{\text{migr}}$ ends up bonded to the inserted oxygen; the non-migrating group ${\text{R}}_{\text{nonmigr}}$ becomes the acyl side of the ester. The net result is oxygen insertion between the carbonyl carbon and the migrating group.

Stage 3. Deprotonation of the oxocarbenium/protonated ester gives the neutral ester or lactone product.

Reagents. Common peracids include $m$CPBA (most widely used; bench-stable solid), peracetic acid, and trifluoroperacetic acid (TFPAA, ${\text{CF}}_3{\text{CO}}_3\text{H}$, more reactive but harder to handle). Hydrogen peroxide with catalytic Lewis acids provides a greener alternative. Enzymatic Baeyer-Villiger monooxygenases (BVMOs) use a flavin hydroperoxide (FAD-OOH) as the biological peracid equivalent.

Stereochemistry. The migrating group migrates with retention of configuration at the migrating centre. This stereochemical outcome is consistent with a concerted sigma-bond migration in which the migrating group never becomes a free carbocation. The configuration at the non-migrating centre is also retained.

Counterexamples to common slips

• "Both groups migrate equally." Migration is highly selective. The migratory aptitude ordering (see Key mechanism below) typically favours one group by a factor of 10 to 1000. The product ratio is kinetically determined by which group migrates faster in the concerted rearrangement.

• "The product ester is determined by which O$-$O bond breaks." Both O$-$O bonds are equivalent in their chemistry; the choice is which C$-$C bond migrates. The O$-$O bond cleaves as the migrating group shifts; it is not an independent event.

• "Aldehydes always give formate esters." Aldehydes usually give carboxylic acids because H has the highest migratory aptitude. The formate ester product (R$-$O$-$CHO) is observed only when the R group has a much higher migratory aptitude than H, which is rare.

• "$\alpha ,\beta$-unsaturated ketones give epoxides." $m$CPBA can epoxidise the alkene, but in BV conditions the carbonyl oxidation is usually faster. The expected product is a vinyl-acetate type ester (vinyl migration dominates over alkyl migration). Peracids are also epoxidation reagents -- side reactions are possible.

Key mechanism Intermediate+

Mechanism (Migratory aptitude ordering). For Baeyer-Villiger oxidation of an unsymmetrical ketone ${\text{R}}_1{\text{-CO-R}}_2$, the group that migrates is determined by the empirically calibrated migratory aptitude series:

$$\text{H}>\text{tert-alkyl}>\text{cyclohexyl}\sim \text{sec-alkyl}>\text{benzyl}\sim \text{phenyl}>\text{primary alkyl}>\text{methyl}$$

The migratory aptitude tracks the ability of the migrating group to stabilise partial positive charge in the transition state, mirroring the order of carbocation stabilities. Groups that stabilise carbocations well (tertiary, benzylic) migrate preferentially over groups that do not (methyl).

Argument. The rate-determining step of the Baeyer-Villiger oxidation is the concerted rearrangement of the Criegee intermediate. In the transition state for this rearrangement, the migrating C$-$C (or C$-$H) bond is partially broken, and the migrating carbon (or hydrogen) develops partial positive charge as it transfers from carbon to the adjacent oxygen:

$${\text{R}}_{\text{migr}}\text{-C(...)}\stackrel{‡}{\to }{\text{R}}_{\text{migr}}^{\delta +}\text{-}\text{O-}\text{C}(...)\text{\hspace{1em}(TS)}$$

By the Hammond postulate (Hammond 1955), the transition state of an endothermic step resembles the products of that step, and the transition state of an exothermic step resembles the reactants. The O$-$O bond cleavage in the Criegee intermediate is endothermic (it costs about 35 kcal/mol to break the O$-$O bond), and the overall rearrangement has a late transition state that resembles the cationic intermediate that would form if the migration were stepwise.

Therefore, factors that stabilise a carbocation on the migrating group also stabilise the transition state. The standard carbocation stability ordering is:

$$\text{tert-carbocation}>\text{secondary}>\text{benzyl}\sim \text{allyl}>\text{primary}>\text{methyl}$$

This matches the migratory aptitude ordering. The migrating group stabilises the partial positive charge in the transition state through hyperconjugation (sigma bonds adjacent to the cationic centre donate electron density), induction (alkyl groups donate by induction), and resonance (benzyl and phenyl groups delocalise the charge through the aromatic pi system).

Quantitatively, the cationic character of the transition state is confirmed by the Brown-Okamoto correlation (see Full proof set): plotting $\log (k_{\text{X}}/k_{\text{H}})$ for para-substituted phenyl migrations against the Brown-Okamoto ${\sigma }^{+}$ constants gives a linear free-energy relationship with reaction constant $\rho \approx -4$ to $-5$. A negative $\rho$ of this magnitude indicates substantial positive charge development on the migrating aryl group in the transition state, consistent with a late, cation-like TS.

Hydrogen migrates fastest because it can stabilise transition-state charge in a different way -- the H$-$C bond that breaks is much higher in energy than a C$-$C bond, and the resulting proton-like partial positive is small and easily accommodated. Additionally, the entropy of activation for H migration is more favourable than for alkyl migration (less conformational ordering required).

Stereochemistry at the migrating centre is retained, ruling out a stepwise mechanism in which the migrating group departs as a free carbocation (which would racemise). The concerted migration is therefore best described as a synchronous sigma-bond shift, with positive charge building on the migrating carbon but never fully localised. $\square$

Bridge. The migratory aptitude ordering is the foundational reason the Baeyer-Villiger oxidation is regioselective rather than regiorandom, and this is exactly the connection that appears again in 15.04.02 SN1 vs SN2 -- in both reactions, the rate is governed by carbocation stability in the transition state, and putting these together identifies the Baeyer-Villiger rearrangement as a 1,2-shift in the same family as the Wagner-Meerwein rearrangement. The bridge is between carbonyl chemistry (the Criegee tetrahedral intermediate) and the broader class of electron-deficient-heteroatom migrations, including the Beckmann rearrangement (oxime to amide) and the Hofmann and Curtius rearrangements (amide to amine with loss of carbonyl carbon), all of which generalise the principle that a group stabilising positive charge migrates preferentially to an electron-deficient centre.

Exercises Intermediate+

Advanced results Master

Theorem 1 (Criegee 1948 mechanistic elucidation). The Baeyer-Villiger oxidation proceeds through a discrete tetrahedral intermediate bearing the peroxy ester linkage $-$O$-$O$-$CO$-$Ar, now called the Criegee intermediate. Criegee isolated derivatives of this intermediate from peracid additions to highly substituted ketones at low temperature and demonstrated that the rearrangement to ester product occurs in a separate step upon warming ^{[Criegee1948]}. The two-step character (addition then rearrangement) is established by the isolation; the rearrangement step is rate-determining.

Theorem 2 (Regiochemistry of cyclic ketone oxidation). For a substituted cyclic ketone, the more substituted alpha carbon migrates preferentially, placing the inserted oxygen between the carbonyl carbon and the less substituted side of the ring. The product is the regioisomer in which the more substituted carbon is alpha to the ester carbonyl of the lactone. This empirical rule, due to the migratory aptitude ordering, is the basis for predicting regioselectivity in complex molecule synthesis.

Theorem 3 (Vinyl migration preference in $\alpha ,\beta$-unsaturated ketones). For an $\alpha ,\beta$-unsaturated ketone $\text{R-CH=CH-CO-R’}$, the vinyl group migrates in preference to the saturated alkyl group $\text{R’}$. The allylic resonance stabilisation of partial positive charge in the transition state lowers the activation barrier for vinyl migration. The product is the vinyl ester, which can be hydrolysed to reveal a 1,3-dicarbonyl equivalent or used in subsequent cross-coupling reactions.

Theorem 4 (Stereoelectronic requirement: antiperiplanar O$-$O to migrating bond). In the Criegee intermediate, the migrating C$-$C bond must be antiperiplanar to the O$-$O bond for the concerted rearrangement to proceed. Conformationally locked cyclic substrates -- where the Criegee intermediate can adopt only specific rotamers -- show dramatically accelerated or decelerated rearrangement depending on whether the antiperiplanar geometry is accessible. This stereoelectronic requirement was elucidated through computational studies (Houk and co-workers, 1980s) and confirmed by kinetic studies on conformationally rigid bicyclic ketones.

Theorem 5 (Brown-Okamoto ${\sigma }^{+}$ correlation). For the Baeyer-Villiger oxidation of para-substituted acetophenones ${\text{p-X-C}}_6{\text{H}}_4{\text{-CO-CH}}_3$, plotting $\log (k_{\text{X}}/k_{\text{H}})$ for the aryl migration pathway against the Brown-Okamoto ${\sigma }^{+}$ constants gives a linear free-energy relationship with reaction constant $\rho \approx -4.5$. The large negative $\rho$ confirms substantial positive charge development on the migrating aryl group in the transition state, consistent with a late, cation-like transition state for the concerted 1,2-shift.

Theorem 6 (Bolm 1994: chiral Lewis-acid catalysed asymmetric BV). Bolm and co-workers (1994) demonstrated that chiral Lewis acid catalysts -- particularly complexes of chiral bipyridine ligands with copper(II) or iron(III) -- catalyse the BV oxidation of cyclic ketones with hydrogen peroxide as the terminal oxidant, giving lactones in moderate to good enantiomeric excess (typically 50--90% ee) ^[Bolm1994]. The chiral Lewis acid coordinates to the ketone, biasing the approach of the peracid (or peroxide) toward one face of the carbonyl, which selects one enantiomeric Criegee intermediate and hence one enantiomeric lactone product.

Theorem 7 (Katsuki 1997: chiral (salen)manganese-catalysed asymmetric BV). Katsuki extended the asymmetric BV to chiral (salen)manganese complexes that give higher enantioselectivities than the Bolm copper systems, particularly for 3-substituted cyclobutanones (substrates that give 5-membered lactones). Enantiomeric excesses exceeding 90% are achieved for several substrate classes ^{[Katsuki1997]}. The Katsuki catalyst operates by a different mechanism from the Bolm system: the manganese activates hydrogen peroxide to form a metal-peroxo intermediate that delivers oxygen to the ketone within the chiral environment of the salen ligand.

Theorem 8 (Walsh 1976: enzymatic BV via FAD hydroperoxide). Cyclohexanone monooxygenase (CHMO), isolated by Walsh and co-workers from Acinetobacter and Cylindrocarpon strains, catalyses the BV oxidation of cyclohexanone to $\epsilon$-caprolactone using ${\text{O}}_2$ and NADPH as cosubstrates ^[Walsh1976]. The active oxidant is a flavin adenine dinucleotide hydroperoxide (FAD-OOH), formed by addition of ${\text{O}}_2$ to the reduced flavin cofactor (FADH). The FAD-OOH acts as the biological peracid equivalent, adding to the substrate carbonyl to form a Criegee intermediate analogous to that in the $m$CPBA reaction. CHMO is highly enantioselective, producing single-enantiomer caprolactone with exquisite regio- and stereoselectivity, and is the prototype of the Baeyer-Villiger monooxygenase (BVMO) enzyme family widely used in biocatalytic synthesis.

Synthesis. The Criegee intermediate builds toward the entire edifice of peracid-mediated oxidation chemistry, and appears again in 15.05.01 as the conceptual neighbour of alkene epoxidation by $m$CPBA -- the same peracid reagent, but adding to a C=C pi bond rather than a C=O pi bond. The foundational reason the migratory aptitude ordering works is that the transition state for the 1,2-shift is cation-like, which is exactly the same physical-organic principle that governs carbocation rearrangements in 15.04.02 SN1 vs SN2 chemistry, and putting these together identifies the BV rearrangement as one member of the broader family of electron-deficient-heteroatom 1,2-migrations (Beckmann, Hofmann, Curtius, Lossen). The central insight is that the choice of peracid ($m$CPBA vs FAD-OOH vs metal-peroxo) determines the catalytic regime but not the underlying mechanism: the Criegee intermediate is invariant across chemical, enzymatic, and asymmetric-catalytic variants. The bridge is between the stoichiometric organic peracid chemistry of 1899 (Baeyer-Villiger) and the modern biocatalytic and asymmetric variants (Walsh 1976, Bolm 1994, Katsuki 1997), which generalises the reaction from a useful synthetic transformation to a paradigm for enzyme mechanism, asymmetric catalysis, and green chemistry.

Full proof set Master

Proposition 1 (Brown-Okamoto correlation derives cation-like transition state). For the Baeyer-Villiger oxidation of a series of para-substituted acetophenones ${\text{p-X-C}}_6{\text{H}}_4{\text{-CO-CH}}_3$ in which aryl migration is observed, the reaction constant $\rho$ in the Hammett-style equation

$$\log \left(\frac{k_{\text{X}}}{k_{\text{H}}}\right)=\rho \cdot {\sigma }_{\text{X}}^{+}$$

takes the value $\rho \approx -4.5$. The large negative value of $\rho$ confirms substantial positive charge development on the migrating aryl group in the transition state.

Proof. The Brown-Okamoto ${\sigma }^{+}$ constants are derived from the solvolysis rates of cumyl chlorides ${\text{p-X-C}}_6{\text{H}}_4{\text{-C(CH}}_3{\text{)}}_2\text{Cl}$, a reaction in which the rate-determining step is unimolecular ionisation to the resonance-stabilised cumyl cation:

$${\text{p-X-C}}_6{\text{H}}_4{\text{-C(CH}}_3{\text{)}}_2\text{Cl}\to [{\text{p-X-C}}_6{\text{H}}_4{\text{-C(CH}}_3{\text{)}}_2{]}^{+}+{\text{Cl}}^{-}$$

The ${\sigma }^{+}$ values incorporate both inductive and resonance effects appropriate for reactions with substantial positive charge development in the transition state, and are calibrated against this reference reaction with $\rho =1$ by definition for cumyl chloride solvolysis.

For a reaction series to correlate linearly with ${\sigma }^{+}$, the rate-determining step must involve positive charge development at a position conjugated with the para substituent on the aromatic ring. In the Baeyer-Villiger rearrangement of the Criegee intermediate from ${\text{p-X-C}}_6{\text{H}}_4{\text{-CO-CH}}_3$, the migrating group is the para-substituted aryl group. The transition state features partial positive charge on the migrating aryl ipso carbon:

$$[{\text{p-X-C}}_6{\text{H}}_4^{\delta +}\cdots \text{O-}\cdots {\text{CO-CH}}_3{]}^{‡}$$

Substituents X that donate electrons by resonance (e.g., $-{\text{OCH}}_3$, $-{\text{N(CH}}_3{\text{)}}_2$) stabilise this partial cation through donation into the aromatic ring, lowering the activation energy and accelerating the reaction. Substituents that withdraw electrons (e.g., $-{\text{NO}}_2$, $-{\text{CF}}_3$) destabilise the partial cation, raising the activation energy.

The slope of the linear free-energy plot, $\rho$, measures the sensitivity of the reaction rate to substituent effects relative to the cumyl chloride reference. A value of $\rho =-4.5$ means the BV reaction is 4.5 times more sensitive to substituent effects than cumyl chloride solvolysis (the negative sign reflects the convention that electron-donating groups accelerate reactions with positive charge in the transition state).

The magnitude $|\rho |=4.5$ is large compared to typical reactions with early or late transition states ($|\rho |$ between 1 and 3). A large $|\rho |$ corresponds to a transition state in which the charge development is nearly complete, i.e. a late transition state resembling the cationic intermediate that would form in a stepwise mechanism. Combined with the observation that the migrating centre retains configuration (ruling out a fully free cation), the picture that emerges is of a synchronous concerted migration with substantial but incomplete charge transfer to the migrating group -- a late, cation-like, but still concerted transition state. $\square$

Proposition 2 (Stereochemical retention at the migrating centre). The concerted 1,2-shift in the Criegee intermediate proceeds with retention of configuration at the migrating stereocentre.

Argument. Consider a chiral migrating centre ${\text{R}}^{\ast }$ bonded to the former carbonyl carbon. In the transition state, the C$-$C bond between ${\text{R}}^{\ast }$ and the carbonyl carbon is partially broken, and the new C$-$O bond between ${\text{R}}^{\ast }$ and the adjacent peroxy oxygen is partially formed. For the migration to be concerted, the same face of ${\text{R}}^{\ast }$ that was bonded to the former carbonyl carbon must form the new bond to oxygen -- the migrating group "slides" from one atom to the other without inversion.

If the mechanism were stepwise (departure of ${\text{R}}^{\ast }$ as a free carbocation, then capture by oxygen), the carbocation would be planar (sp${}^2$) at the cationic centre, and capture by oxygen could occur from either face, leading to racemisation. The observation of complete retention in numerous stereochemical experiments (Krow 1993 review; Bolm 1994 asymmetric BV) rules out this stepwise pathway.

The retention is therefore diagnostic of a concerted sigma-bond migration, in which the migrating group, the oxygen it migrates to, and the leaving carboxylate are all aligned in a single transition-state geometry -- the antiperiplanar arrangement of Theorem 4 above. $\square$

Connections Master

• Carbonyl chemistry — nucleophilic addition 15.07.01. The Criegee intermediate in the Baeyer-Villiger oxidation is a tetrahedral species directly analogous to the tetrahedral alkoxide intermediates that appear in nucleophilic addition of organometallic reagents and hydrides to carbonyls. The foundational difference is that the BV intermediate bears a peroxy ester substituent that becomes a leaving group, whereas standard nucleophilic addition intermediates are protonated and trapped as alcohols. The Criegee intermediate builds toward 15.07.02 pending acyl substitution chemistry, where tetrahedral intermediates also collapse by expelling a leaving group from the carbonyl carbon.

• SN1 vs SN2 substitution mechanisms 15.04.02. The migratory aptitude ordering in the Baeyer-Villiger oxidation (H > tert-alkyl > sec-alkyl > benzyl ~ phenyl > primary > methyl) tracks the carbocation stability ordering that governs SN1 rates. The foundational reason for this parallel is the Hammond-postulate argument that the BV transition state is cation-like; this is exactly the same physical-organic principle that predicts which substrates undergo SN1 vs SN2 substitution. The Brown-Okamoto $\rho \approx -4.5$ correlation quantitatively confirms this cationic character, just as Hammett correlations in solvolysis confirm the SN1 mechanism.

• Electrophilic addition to alkenes 15.05.01. The peracid reagent $m$CPBA used in Baeyer-Villiger oxidation is the same reagent used in alkene epoxidation, where it adds an oxygen across a C=C double bond to give an epoxide. The two reactions are mechanistically distinct (BV adds to C=O via the Criegee intermediate and migratory rearrangement; epoxidation adds to C=C via a concerted "butterfly" mechanism with no intermediate), but the shared reagent unifies them under the broader umbrella of peracid oxidation chemistry. The choice of substrate (C=O vs C=C) determines which pathway dominates; in substrates with both functional groups, chemoselectivity can be tuned by reaction conditions.

• Aromatic chemistry — EAS, Huckel 15.06.01. Phenyl ketones ($\text{Ar-CO-R}$) undergo Baeyer-Villiger oxidation with aryl migration to give phenyl esters ($\text{Ar-O-CO-R}$), not alkyl migration to give alkyl benzoates. The aromatic ring migrates because its pi system can stabilise the partial positive charge in the transition state through resonance delocalisation across the ring. The Brown-Okamoto correlation with ${\sigma }^{+}$ constants (rather than $\sigma$) is diagnostic: ${\sigma }^{+}$ incorporates resonance donation effects appropriate for reactions with cationic character conjugated to the aromatic ring, providing the bridge between the migratory aptitude of aryl groups and the electrophilic aromatic substitution reactivity patterns treated in 15.06.01.

Historical & philosophical context Master

Adolf von Baeyer and Victor Villiger reported the peracid oxidation of cyclic ketones to lactones in 1899 ^{[BaeyerVilliger1899]} in Berichte der Deutschen Chemischen Gesellschaft, vol. 32, page 3625. Their original observation used Caro's acid (peroxymonosulfuric acid, ${\text{H}}_2{\text{SO}}_5$, made from ${\text{H}}_2{\text{O}}_2$ and sulfuric acid) as the oxidant. They noted the ring expansion of cyclic ketones and the formation of lactones, but the mechanism was not established in their original paper; for several decades the reaction was treated as an empirical transformation without a clear mechanistic picture.

Rudolf Criegee provided the modern mechanistic elucidation in a series of papers beginning in 1948, most notably in Liebigs Annalen der Chemie vol. 560 (1948) and vol. 564 (1949) ^{[Criegee1948]}. Criegee isolated derivatives of the tetrahedral peroxy-ester intermediate at low temperature from highly substituted ketones and demonstrated that the rearrangement to the ester product is a separate, slower step. The intermediate has since borne his name. Criegee's mechanistic work, parallel to his earlier contributions to ozonolysis and lead tetraacetate oxidation, established the template for the modern physical-organic understanding of peracid chemistry: addition to give a tetrahedral intermediate, followed by a concerted 1,2-shift with concomitant leaving-group departure.

The mechanistic picture was completed in the second half of the 20th century. The stereochemical retention at the migrating centre was established by Doering and Speers (1950) and by Cram (1952). The Brown-Okamoto ${\sigma }^{+}$ correlation (Brown and Okamoto, J. Am. Chem. Soc. 1958, 80, 4979) quantified the cation-like character of the transition state. The stereoelectronic antiperiplanar requirement was elucidated by Houk and co-workers using ab initio calculations in the 1980s. The asymmetric BV was introduced by Bolm in 1994 ^[Bolm1994] using chiral copper catalysts and extended by Katsuki in 1997 ^{[Katsuki1997]} with chiral (salen)manganese complexes. The enzymatic Baeyer-Villiger oxidation was elucidated by Walsh and co-workers beginning in 1976 ^[Walsh1976], who characterised cyclohexanone monooxygenase (CHMO) and established the FAD-OOH mechanism that underlies all Baeyer-Villiger monooxygenases (BVMOs), now widely used in biocatalytic synthesis.

Bibliography Master

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}

@book{Clayden2012,
  author = {Clayden, J. and Greeves, N. and Warren, S.},
  title = {Organic Chemistry},
  edition = {2nd},
  publisher = {Oxford University Press},
  year = {2012}
}

@book{McMurry2020,
  author = {McMurry, J. E.},
  title = {Organic Chemistry},
  edition = {10th},
  publisher = {Cengage Learning},
  year = {2020}
}