The synthesis of 1-(m-nitrophenyl)diazonium chloride from m-nitroaniline is a good example of the standard laboratory procedure for the transformation of an amine into a diazonium salt.

Concentrated hydrochloric acid (125 mL) and 250 mL of hot water are added to m-nitroaniline (138 g, 1.0 mol). The resulting solution is heated to 85 °C followed by the addition of 275 mL of concentrated hydrochloric acid. The reaction mixture is then cooled rapidly in a salt-ice bath. A solution of sodium nitrite (72 g, 1.05 mol) in 175 mL of water is then added slowly below the surface of the reaction mixture with stirring. The temperature of the reaction mixture is monitored to maintain the temperature below 0 °C. The resulting solution is then stirred for an additional 20 minutes followed by the slow addition of urea (5g) in 12.5 mL of water over 15 minutes to minimize foaming. The resulting solution of 1-(m-nitrophenyl)diazonium chloride is not isolated and should be kept cold until it used in a subsequent step.

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.

While in its traditional form the Finkelstein reaction involves the transformation of an alkyl chloride or bromide to the corresponding alkyl iodide via treatment with sodium iodide in acetone, the name also refers to the conversion of alkyl sulfonates to alkyl iodides. Alkyl sulfonates are readily prepared from alcohols.

Procedure:

A solution of 5-hexen-1-ol (5.0 g, 0.050 mol) and triethylamine (7.6 g, 0.076 mol) in 250 mL of dichloromethane is cooled under inert atmosphere in an ice salt bath to ca. -5 °C. Methanesulfonyl chloride (4.7 mL, 0.06 mol) is added dropwise with stirring. After stirring for an additional hour at ca. -5 °C, the reaction is washed with cold water, cold 10% aqueous hydrochloric acid, a cold saturated aqueous solution of sodium bicarbonate, and a cold solution of brine using approximately 75 mL for each wash. The organic fraction is dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the mesylate which is used in the next step without further purification.

To the flask containing the unpurified mesylate product are added 100 mL of dry acetone followed by anhydrous sodium iodide (9.3 g, 0.06 mol) with stirring under inert atmosphere. After stirring at reflux for 4 hours the reaction mixture is cooled to ambient temperature. The resulting solution is concentrated in vacuo and treated with 25 mL of pentane and 25 mL of 10 % aqueous sodium thiosulfate. The organic fraction is washed with 25 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude material is then passed through a plug of silica gel and eluted with pentane. The solution is then concentrated in vacuo to afford the title compound.

http://www.orgsyn.org/orgsyn/prep.asp?prep=v81p0121

This synthesis is a straightforward example of a laboratory procedure for the Mannich reaction. All of the reagents are combined together and the reaction is performed in a single pot. The electrophilic iminium ion is generated by the acid-promoted condensation of formaldehyde and dimethylamine in the presence of acetophenone and is consumed as it is formed.

A solution of acetophenone (30.0 g, 28.3 mL, 0.25 mol), dimethylamine hydrochloride (26.5 g, 0.33 mol), and paraformaldehyde (9.9 g, 0.11 mol) is treated with 0.5 mL of concentrated hydrochloric acid in 40 mL of 95% ethanol. The solution is heated to reflux for 2 hours followed by rapid filtration through a preheated funnel. The warm solution is treated with 100 mL of acetone and is then allowed to cool to room temperature slowly. After cooling for 12 hours at 0 °C, the solution is filtered to afford the title compound. Alternatively the crude material can be purified via column chromatography.

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0305

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.

4-(Diethylamino)butan-2-one

The Mannich Reaction remains a popular tool in organic synthesis. It performs a one-carbon homologation and an amination in a single step and is involved in the biosynthetic pathways in the synthesis of many alkaloid natural products.

A very simple example of the reaction is the synthesis of 4-(diethylamino)butan-2-one. A solution of diethylamine hydrochloride (88.0 g, 0.80 mol), paraformaldehyde (34.0 g, 1.13 mol), acetone (300 mL, 4.1 mol), 40 mL of methanol, and 0.1 mL of concentrated hydrochloric acid is stirred at reflux using an oil bath for 12 hours. The reaction mixture is then allowed to cool to ambient temperature. A solution of sodium hydroxide (32.5 g) in 150 mL is then cooled to 0 °C and added to the reaction mixture. The resulting solution is extracted with diethyl ether (3X100 mL) and the combined organic fractions are washed with brine. The combined aqueous layers are then washed with diethyl ether (2X75 mL).

The combined organic fractions are dried over magnesium sulfate, filtered, and purified via vacuum distillation. The title compound is collected in fractions at approximately 63-67 °C at 15 mm of pressure.

The Williamson Ether synthesis continues to be an important reaction in organic synthesis. The procedure is simple and usually produces the desired compound in high overall yield. It is therefore frequently employed to introduce ether protective groups and ether functional groups in natural products.

The synthesis of 3-(2-methoxyethoxy)prop-1-ene from 2-methoxyethanol and allyl bromide is an excellent example of the procedure. In this case the electrophilic organobromide species is allyl bromide. Allyl bromide is much more reactive than a simple primary alkyl halide because the incipient positive charge that develops as the carbon undergoes nucleophilic attack can be delocalized by the π-orbital of the carbon-carbon double bond. Benzyl bromide also enjoys an increased reaction rate because the positive charge can be stabilized by the π-system of the aromatic ring. The Williamson Ether synthesis can proceed through either the S_N1 or S_N2 mechanism with these reagents, whereas simple primary alkyl halides such as ethyl bromide generally can only proceed through the S_N2 mechanism.

Procedure: 3-(2-methoxyethoxy)prop-1-ene

A solution of potassium hydroxide (25.5 g, 0.45 mol) in dry 2-methoxyethanol (32.5 mL, 31.15 g, 0.41 mol) is cooled to 0 °C. The reaction temperature is maintained below 10 °C as allyl bromide (36 mL, 25.0 g, 0.41 mol) is added dropwise with rapid stirring over several minutes. The reaction is then allowed to warm slowly to room temperature and is stirred for 10 hours at ambient temperature. The resulting mixture is then filtered and the solids are washed with 150 mL pentane in small portions. The combined organic fractions are dried over magnesium sulfate. Fractional distillation over calcium hydride provides the title compound in fractions collected between approximately 115-129 °C.

A good example of an application of the Friedel-Crafts acylation is the synthesis of 1,1-diphenylacetone. The compound is readily prepared in two steps from phenylacetone. In the first step, phenylacetone is converted to 1-bromo-1-phenylacetone via radical bromination. Bromination occurs at the carbon adjacent to the phenyl ring. The energy barrier to forming a radical at the carbon adjacent to the phenyl ring is substantially lower than the energy barrier to forming a radical at the other sp3 hybridized carbon atom; therefore, this species predominates and leads to the formation of the observed product.

Preparation: Aluminum trichloride (37.5 g, 0.28 mol) is combined with 75 mL of dry benzene under inert atmosphere. The mixture is heated at reflux and a solution of 1-bromo-1-phenylacetone (59.0 g, 0.28 mmol) in 100 mL of benzene was added dropwise over a period of 1 hour. The mixture is heated at reflux for 1 hour after the addition is complete. The reaction mixture is then cooled and poured into a mixture of 50 mL of concentrated HCl in 250 g of ice. The resulting mixture is then allowed to warm slowly to room temperature and the aqueous layer is washed with diethyl ether.

The combined organic fractions are washed with water followed by a saturated aqueous solution of sodium bicarbonate. The resulting solution is then dried over magnesium sulfate and concentrated in vacuo. The resulting crude product can be purified via fractional distillation or flash chromatography to afford the title compound.

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 synthesis of ethyl 5-iodovalerate, the ethyl ester of 5-iodovaleric acid, is an excellent example of a practical application of the Finkelstein reaction in organic synthesis. Alkyl iodide compounds are generally more reactive than the corresponding alkyl bromides in a number of reactions that involve the formation of an organometallic intermediate (e.g. the Grignard Reaction). Alkyl iodides are generally less stable than the corresponding bromides, however. In order to take advantage of the greater long-term stability of the bromides and the greater reactivity of the alkyl iodides, the iodides are frequently generated immediately prior to use.

Ethyl 5-iodovalerate can readily be prepared from the corresponding commercially available bromide via reaction with sodium iodide in acetone. Ethyl 5-bromovalerate (6.25g, 29.8 mmol) is dissolved in 75 mL of dry acetone. Sodium iodide (22.4g, 150 mmol) is then added in small portions over several minutes. The solution is heated to reflux for 48 h followed by cooling to ambient temperature. The resulting mixture is combined with 100 mL of diethyl ether and 100 mL of water. The resulting aqueous phase is extracted with diethyl ether (3X50 mL). The combined organic layers are then washed with 25 mL of a 10% aqueous solution of sodium bisulfite followed by 25 mL of brine. The resulting solution is then dried via magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is purified via vacuum distillation to afford the iodide. The product can be stored over copper wire to improve shelf life.