The Baeyer-Villiger oxidation is a transformation in organic chemistry that inserts an oxygen atom between the carbonyl carbon of a ketone and an adjacent carbon atom:

The reaction is often performed using a peroxyacid such as mCPBA (meta-chloroperbenzoic acid). Other oxidants can be used under certain circumstances including hydrogen peroxide, peroxyacetic acid, peroxytrifluoroacetic acid, and other organic peroxy acids and peroxides.

Mechanism:

The mechanism involves the acid-promoted nucleophilic attack of the carbonyl carbon atom of the ketone starting material by the oxygen atom of the peroxy acid that is not bonded to carbon. This produces the tetrahedral intermediate known as the Criegee intermediate. A pair of electrons on the oxygen atom in the species formed is then used to form a carbon oxygen double bond, and one of the alkyl groups undergoes a 1,2 shift from the carbon atom of the carbonyl to the oxygen atom of the peroxy acid. The carboxylate analog of the peroxy acid is eliminated and the resulting ester product is formed.

Regio- and Stereochemistry:

The regiochemistry and stereochemistry of the reaction products are highly predictable. The group that migrates is the group that is best able to stabilize a developing positive charge in the transition state. Usually, but not always, the more highly substituted group will migrate. If one of the groups is particularly capable of stabilizing a positive charge, such as allyl or benzyl, it will usually migrate even if it is not the most highly substituted group. When the carbon atom that migrates is an asymmetric (i.e. chiral) center, the reaction usually proceeds with retention of configuration.

When aldehydes are subjected to the reaction conditions the hydrogen atom attached to the carbonyl carbon usually migrates and gives rise to the carboxylic acid. If the group attached to carbon is particularly well suited to stabilize a positive charge however, that group may undergo migration to produce the formic acid ester (i.e. formate).

References:

Baeyer, A.; Villiger, V. “Einwirkung des Caro’schen Reagens auf Ketone” (abstract). Ber. 1899, 32 (3): 3625–3633.

Burton, J.W.; Clark, J.S.; Derrer, S.; Stork, T.C.; Bendall, J.G.; Holmes, A.B. “Synthesis of Medium Ring Ethers. 5. The Synthesis of (+)-Laurencin” (Abstract). J. Am. Chem. Soc. 1997, 119 (32): 7483–7498.

M. A. Goodman, M. R. Detty. “Selenoxides as Catalysts for Epoxidation and Baeyer-Villiger Oxidation with Hydrogen Peroxide” Synlett, 2006, 1100-1104.

S. Murahashi, S. Ono, Y. Imada, Angew. “Asymmetric Baeyer-Villiger Reaction with Hydrogen Peroxide Catalyzed by a Novel Planar-Chiral Bisflavin” Chem. Int. Ed., 2002, 41, 2366-2368.

G. A. Olah, Q. Wang, N. J. Trivedi, G. K. S. Prakash. “Baeyer-Villiger Oxidation of Ketones to Esters with Sodium Percarbonate/Trifluoroacetic Acid”, Synthesis, 1991, 739-740.

Michael Renz, Bernard Meunier (1999). “100 Years of Baeyer-Villiger Oxidations”. European Journal of Organic Chemistry 1999 (4): 737–750.

An example of the experimental procedure of the Dieckmann condensation is exemplified by the synthesis of 3-quinuclidone hydrochloride. This preparation involves two steps. In the first step, 1-((ethoxycarbonyl)methyl)-4-carbethoxypiperidine is treated with potassium ethoxide in refluxing toluene leading to the formation of the bridgehead bicyclic system via the Dieckmann condensation. In the second step, the intermediate is decarboxylated via treatment with concentrated hydrochloric acid.

Experimental:

3-Quinuclidone hydrochloride

1. Dieckmann Condensation:

Freshly cut potassium (40 g, 1.03 mol) is added to 165 mL of dry toluene under inert atmosphere. The mixture is heated at reflux until the potassium has melted. Absolute ethanol (63 mL, 49.3 g, 1.07 mol) is then added over 30 minutes to the rapidly stirred solution at reflux. Upon the disappearance of the potassium metal, the temperature of the reaction mixture is raised to 130 °C and 1-((ethoxycarbonyl)methyl)-4-carbethoxypiperidine (100 g, 0.411 mol) in 250 mL of dry toluene is added dropwise over 2 hours.

After heating at 130 °C for an additional 3 hours, the reaction mixture is cooled to 0 °C followed by slow addition of 250 mL 10M hydrochloric acid. The resulting mixture is then extracted with 10M hydrochloric acid (2X125 mL).

2. Decarboxylation:

The combined aqueous fractions are heated at reflux for 15 hours followed by the addition of 5 g of activated charcoal. The resulting mixture is then filtered and evaporated to dryness in vacuo. The crude product is then dissolved in 150 mL of water and saturated aqueous potassium carbonate is added very slowly to avoid foaming until the solution has become basic. The resulting solution is then treated with solid potassium carbonate until a slurry is obtained, followed by extraction with diethyl ether (4X200 mL). The combined organic fractions are then treated with calcined potassium carbonate. After 60 minutes the mixture is filtered and concentrated in vacuo. The resulting solid is then treated with 75 g of ice and 10M hydrochloric acid (65 mL, 75 g) followed by evaporation to dryness. The resulting material is then purified via recrystallization from hot water and boiling isopropanol.

The Dieckmann Condensation is an intramolecular variant of the Claisen Condensation. The reaction is most commonly used to prepare 5 or 6 membered ring ß-keto esters. The formation of 5 membered rings tends to be faster than 6 membered rings, although the 6 membered ring products are generally more thermodynamically stable. Ring formation becomes progressively more difficult to accomplish as the ring size of the desired product increases.

The reaction typically employs the sodium alkoxide of the alcohol that corresponds to the alcoholic moiety of the ester functional groups. The reaction can also be promoted by the use of one equivalent of sodium hydride and a catalytic amount of the corresponding alcohol.

The Dieckmann Condensation generally cannot be used to prepare small, highly strained ring systems. Rather than form a three membered ring, diethyl succinate undergoes an intermolecular Claisen Condensation followed by a Dieckmann Condensation to afford the six membered ring compound instead of reacting to form the three membered ring ß-keto ester as shown below.

See 3-quinuclidone hydrochloride for an example of a laboratory procedure for the Dieckmann condensation.

References:
Dieckmann, W. Ber., 1894, 27, 102, 965.
Dieckmann, W. Ber., 1900, 33, 595, 2670.
Dieckmann, W. Ann., 1901, 317, 51, 93.
Schaefer, J.P.; Bloomfield, J.J. Org. React., 1967, 15, 1-203.
J. Org. Chem., 1998, 63, 4069-4078.
T. R. Hoye, V. Dvornikovs, E. Sizova, Org. Lett., 2006, 8, 5089-5091.
Davis, B. R.; Garrett, P. J. Comp. Org. Syn. 1991, 2, 806-829. (Review)
Janice Gorzynski Smith. Organic Chemistry: Second Ed. 2008. pp 932-933.

The Claisen Condensation is an important carbon-carbon bond forming reaction that produces a 1,3-dicarbonyl compound from an ester and another carbonyl compound. The intramolecular variant of the reaction is known as the Dieckmann Condensation. The reaction is performed under basic conditions, usually using the alkoxide form of the alcohol component of the ester to avoid transesterification.

The reaction usually involves the reaction of two molecules of the same ester to avoid forming a mixture of different condensation products. An ester and a different carbonyl compound can be used however, particularly when the ester does not possess an enolizable hydrogen atom α to the carbonyl. This variant is known as the Crossed Claisen Condensation.

The mechanism involves formation of the enolate of the compound that will react with the ester as a nucleophile. The enolate is formed via deprotonation of a hydrogen atom α to the carbonyl. The enolate then attacks the carbonyl carbon of the ester, and the tetrahedral intermediate undergoes elimination of alkoxide.

The driving force of the reaction is the deprotonation of the resulting 1,3-dicarbonyl compound condensation product. Hydrogen atoms that are α to two carbonyl carbon atoms are significantly more acidic than either the alcohol or the starting materials and essentially all of the 1,3-dicarbonyl product will be deprotonated in solution. For example, the pKa of ethyl acetoacetate (shown above) is 11, whereas the pKa of ethanol is 16.

The Claisen Condensation differs from the Aldol Condensation because the Aldol Condensation forms an intermediate β-hydroxy carbonyl compound which undergoes elimination to form an α,β-unsaturated carbonyl compound. In the Claisen Condensation however, the resulting tetrahedral intermediate is a hemiketal which can eliminate alkoxide to form the ketone.

Esters are a class of functional groups and chemical compounds. Esters consist of an organic or inorganic acid in which the -OH group of the acid is replaced by an -OR group. Cyclic esters are usually called lactones. Some acids that are commonly esterified are carboxylic acids, phosphoric acid, nitric acid, and sulfuric acid. Volatile esters, particularly carboxylate esters, often have a pleasant smell and are found in essential oils, perfumes, and pheromones, and give many fruits their characteristic scent. Methyl acetate and ethyl acetate are important solvents; phosphoesters form the backbone of DNA molecules; fats and lipids are the esters of fatty acids; and polyesters are important synthetic fabrics and plastics. Esters can be synthesized in a condensation reaction between an acid and an alcohol in a reaction known as esterification.

Nomenclature

An ester is named according to the two parts that make it up: the part from the alcohol and the part from the acid (in that order), for example ethyl ethanoate (see image below).

For esters derived from the simplest carboxylic acids, the traditional name for the acid constituent is generally retained; for example, formate, acetate, propionate, butyrate. For esters from more complex carboxylic acids, the systematic name for the acid is used, followed by the suffix -oate. For example, methyl formate is the ester of methanol and methanoic acid (formic acid). It could also be called methyl methanoate.

Physical properties

Esters participate in hydrogen bonds as hydrogen-bond acceptors, but unlike their parent alcohols cannot act as hydrogen-bond donors. This ability to participate in hydrogen bonding makes them more water-soluble than their parent hydrocarbons; however, the limitations on their hydrogen bonding also make them more hydrophobic than either their parent alcohols or their parent acids. Their lack of hydrogen-bond-donating ability means that ester molecules cannot hydrogen-bond to each other, which, in general, makes esters more volatile than a carboxylic acid of similar molecular weight. This property makes them very useful in organic analytical chemistry: Unknown organic acids with low volatility can often be esterified into a volatile ester, which can then be analyzed using mass spectrometry, gas chromatography, or gas liquid chromatography. Many esters have distinctive odors and are used as artificial fragrances and flavorings.

Reactions

• Saponification (basic hydrolysis)
• Hydrolysis - the breakdown of an ester by water. This process can be catalyzed by both acids and bases. The base-catalyzed process is called saponification. The hydrolysis yields an alcohol and a carboxylic acid or its carboxylate salt.
• Reaction with primary or secondary amines to form amides.
• Phenyl esters react to form hydroxyarylketones via the Fries rearrangement.
• Esters are converted to isocyanates through intermediate hydroxamic acids in the Lossen rearrangement.
• Di-ester enolates such as diethyl malonate react as nucleophiles with alkyl halides in the malonic ester synthesis.
• Certain esters are functionalized with an α-hydroxyl group via the Chan rearrangement.
• Esters with β-hydrogen atoms can be converted to alkenes via pyrolysis.

Synthesis

Methods of preparing esters include:

• Transesterification.
• Dieckmann condensation or Claisen condensation.
• Favorskii rearrangement of α-haloketones in the presence of base.
• Pinner reaction of a nitrile with an alcohol.
• Nucleophilic displacement of alkyl halides with carboxylic acid salts.
• Nucleophilic displacement of acyl halides with alcohols.
• Baeyer-Villiger oxidation of ketones with peroxides.