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.

The Friedel-Crafts acylation is an example of an electrophilic aromatic substitution reaction. The overall transformation involves the displacement of an aryl hydrogen atom with an acyl moiety derived from the corresponding acyl chloride. The product of the reaction is an alkyl aryl ketone.

The acyl chloride is first converted to the acylium ion intermediate by reacting it with a Lewis acid catalyst such as aluminum trichloride. The Lewis acid coordinates to the chloride and the activated chloride ion is then eliminated to produce the acylium ion. The acylium ion is now sufficiently electrophilic to undergo nucleophilic attack by the π-system of the aromatic ring. Deprotonation at the aryl carbon that now bears the acyl group restores aromaticity and a neutral charge to the aromatic ring.

The acyl aromatic compound produced by the Friedel-Crafts acylation can undergo a number of different transformations and functional group manipulations. The carbonyl moiety can be reduced to a methylene by means of either the Clemmensen Reduction or the Wolff-Kishner Reduction. This sequence of reactions is formally equivalent to the Friedel-Crafts alkylation but does not suffer from the same problems such as carbocation rearrangements and polyalkylation.

The Friedel-Crafts alkylation reaction is related to the acylation in that both reactions are electrophilic aromatic substitution reactions and both employ aluminum trichloride to activate an organohalide. The starting material for the alkylation is an alkylhalide and the reaction introduces an alkyl group to the aromatic ring. See the synthesis of 1,1-diphenylacetone for an example of the laboratory procedure for this reaction.

The Finkelstein reaction involves the reaction of an alkyl chloride or bromide with sodium iodide to produce the corresponding alkyl iodide. The reaction may proceed via either an S_N1 or S_N2 mechanism depending on the nature of the alkyl halide.

Mechanism:

Acetone is employed as solvent in the classical version of the reaction. Acetone is used in order to take advantage of the relatively higher solubility of sodium iodide compared to sodium bromide or chloride. The precipitation of the chloride or bromide salts removes the ions from solution and drives the reaction to completion. In the synthesis of ether compounds, the reaction can be used to prepare a suitable alkyl iodide for use in the Williamson Ether Synthesis.

The reaction can also be performed in other solvents and the reaction can be driven to completion by the addition of a large excess of iodide. The reaction can also be employed using a catalytic amount of iodide. The alkyl iodide product can be generated in situ where it reacts further, regenerating the iodide.

The relative rates of reactivity of various alkyl halides in the Finkelstein reaction resembles the rates of reactivity observed in other nucleophilic substitution reactions. The reaction rate increases as the number of carbons bonded to the carbon atom bearing the halogen decreases. The reaction rate is significantly higher when the carbon atom that undergoes attack is adjacent to a double bond or aromatic ring. Allyl bromide and benzyl bromide have a much higher rate of reaction than simple primary alkyl halides such as ethyl bromide. Electron donors on such double bonds or aromatic rings tend to increase the rate of reaction. Electron withdrawing groups tend to decrease the rate. This is consistent with a transition state that places a developing positive charge on the carbon atom undergoing attack.

One variant of the reaction involves converting an alcohol to an excellent leaving group such as a tosylate, and then converting the tosylate to the iodide. This sequence formally has the effect of converting an alcohol to an alkyl halide.

Experimental Procedure:

For an example of the laboratory procedure for the Finkelstein reaction, see the synthesis of ethyl 5-iodovalerate.

References:

H. Fickelstgein, Ber., 1910, 43, 1528.

C. K. Ingold, Structure and Mechanisms in Organic Chemistry (Cornell Univ. Press, London, 2nd ed., 1969) p. 435.

Streitwieser, A. Chem. Rev., 1956, 56, 571.

J. Hayami et al., Tetrahedron Letters, 1973, 385.

S. Samaan, F. Rolla, Phosphorus and Sulfur, 4, 145 (1978).

W. B. Smith, G. D. Branum, Tetrahedron Letters, 1981, 22, 2055.

F. G. Bordwell, W. T. Brannen, J. Am. Chem. Soc., 1964, 86, 4645.

D. W. Kim, C. E. Song, D. Y. Chi, J. Org. Chem., 2003, 68, 4281-4285.

T. W. Baughman, J. C. Sworen, K. B. Wagener, Tetrahedron, 2004, 60, 10943-10948.

Maloney, D. J. Hecht, S. M. Org. Lett., 2005, 7, 4297.

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.

The Aldol Condensation is one of the most fundamental carbon-carbon-bond forming reactions in organic synthesis. Two carbonyl compounds, each of which may be either an aldehyde or a ketone, undergo a base-promoted condensation to afford an α,β-unsaturated carbonyl compound.

The reaction takes place in two stages. First, the enol form of one of the carbonyl compounds attacks the non-enolized carbonyl carbon atom of the second compound. This results in the formation of a β-hydroxy carbonyl compound. In the second stage, the intermediate tautomerizes to the enol form and a molecule of water is eliminated. This second step is possible only if the first enolizable compound possesses two hydrogen atoms on a carbon adjacent to the carbonyl because it must be able to tautomerize to the enol form twice. If only one such hydrogen atom is present, the reaction can proceed no farther than the β-hydroxy carbonyl compound.

Scheme:

The Mannich Reaction is an important carbon-carbon-bond forming reaction that is commonly employed in the synthesis of alkaloid natural products and is involved in a number of biosynthetic pathways. The reaction uses three components: an amine, a non-enolizable aldehyde or ketone, and a compound containing an enolizable carbonyl moiety. The final product of the reaction is a β-amino-carbonyl compound.

Mechanism:

The amine and non-enolizable aldehyde or ketone react to form an iminium ion or “Schiff base”. The second carbonyl compound tautomerizes to the enol form and attacks the iminium ion at the electrophilic carbon atom. The reaction typically requires long reaction times and elevated temperature under acidic conditions.

The reaction has continued to enjoy frequent use by synthetic chemists and has been employed in a several of the most important accomplishments in organic synthesis including strychnine, quinine, and atropine. The reaction has been extended by the discovery that a catalytic amount of (S)-proline, an inexpensive and naturally occurring amino acid, can be used to control the stereoselectivity of the reaction and provide products with high ee (enantiomeric excess).

Experimental Procedure:

For an example of the laboratory procedure for the Mannich reaction, see the synthesis of 4-(diethylamino)butan-2-one.

References:

Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III (2002). “A Highly Enantioselective Route to Either Enantiomer of Both α- and β-Amino Acid Derivatives”. Journal of the American Chemical Society 124 (9): 1866–1867. doi:10.1021/ja017833p.

Mannich, C.; Krosche, W. (1912). “Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin”. Archiv der Pharmazie 250: 647–667. doi:10.1002/ardp.19122500151.

Mitsumori S., Zhang H., Ha-Yeon Cheong P., Houk K. N.,Tanaka F., Barbas III C. F. (2006). “Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid”. Journal of the American Chemical Society 128 (4): 1040–1041. doi:10.1021/ja056984f.

The Williamson ether synthesis is a nucleophilic substitution reaction that leads to the formation of an ether by reacting an alkyl halide with an alkoxide ion:

The reaction can also be used to prepare an ether from two alcohol starting materials by first converting the OH moiety on one of the alcohols to a better leaving group such as tosylate, nosylate, brosylate, trifluoromethanesulfonate, or other sulfonate.

The reaction works best with primary alkyl halides and alcohols. Tertiary alkyl halides will not undergo an S_N2 displacement. Depending on the alkoxide, either elimination products (by either an E1 or E2 mechanism) or S_N1 products generally will be observed.

Mechanism:

The reaction proceeds primarily through an S_N2 (second order nucleophilic substitution) mechanism, particularly when a primary alkyl halide is used. The reaction can also proceed through an S_N1 (first order nucleophilic substitution) mechanism. E1 and E2 elimination products can also be observed when secondary alkyl halides are used.

The reaction rate for alkyl chlorides and bromides can be improved by adding a catalytic amount of sodium iodide to the reaction in a variation known as the Finkelstein reaction. The highly nucleophilic iodide ion displaces chloride or bromide to form an alkyl iodide intermediate which then reacts with the alkoxide.

Experimental Procedure:

See 3-(2-methoxyethoxy)prop-1-ene for an example of the laboratory procedure.