Organic Reactions.pdf

Arndt-Eistert Synthesis

The Arndt-Eistert Synthesis allows the formation of homologated carboxylic acids or their

derivatives by reaction of the activated carboxylic acids with diazomethane and subsequent Wolff-

Rearrangement of the intermediate diazoketones in the presence of nucleophiles such as water,

alcohols, or amines.

Mechanism of the Arndt-Eistert Synthesis

In the first step of this one-carbon homologation, the diazomethane carbon is acylated by an acid

chloride or mixed anhydride, to give an α-diazoketone . The excess diazomethane can be destroyed

by addition of small amounts of acetic acid or vigorous stirring. Most α-diazoketones are stable and

can be isolated and purified by column chromatography (see recent literature for specific methods).

The key step of the Arndt-Eistert Homologation is the Wolff-Rearrangement of the diazoketones to

ketenes, which can be accomplished thermally (over the range between r.t. and 750°C [Zeller,

Angew. Chem. Int. Ed. , 1975 , 14 , 32. DOI ] ), photochemically or by silver(I) catalysis. The reaction

is conducted in the presence of nucleophiles such as water (to yield carboxylic acids), alcohols (to

give alcohols) or amines (to give amides), to capture the ketene intermediate and avoid the

competing formation of diketenes.

The method is widely used nowadays for the synthesis of β-amino acids . Peptides that contain β-

amino acids feature a lower rate of metabolic degradation and are therefore of interest for

pharmaceutical applications.

Wolff Rearrangement

The Wolff Rearrangement allows the generation of ketenes from α-diazoketones . Normally, these

ketenes are not isolated, due to their high reactivity to form diketenes.

Wolff rearrangements that are conducted in the presence of nucleophiles generate derivatives of

carboxylic acids, and in the presence of unsaturated compounds can undergo [2+2] cycloadditions

(for example Staudinger Synthesis ) .

The formation of α-diazoketones from carboxylic acids (via the acyl chloride or an anhydride) and

the subsequent Wolff Rearrangement in the presence of nucleophiles results in a one-carbon

homologation of carboxylic acids. This reaction sequence, which first showed the synthetic

potential of the Wolff-Rearrangement, was developed by Arndt and Eistert .

Mechanism of the Wolff Rearrangement

α-Diazoketones undergo the Wolff Rearrangement thermally in the range between room

temperature and 750 °C in gas phase pyrolysis. Due to competing reactions at elevated

temperatures, the photochemical and metal-catalyzed variants that feature a significantly lowered

reaction temperature are often preferred (Zeller, Angew. Chem. Int. Ed. , 1975 , 14 , 32. DOI ) .

Nitrogen extrusion and the 1,2-shift can occur either in a concerted manner or stepwise via a

carbene intermediate:

Silver ion catalysis fails with sterically hindered substrates, pointing to the requisite formation of a

substrate complex with the ion. In these cases, photochemical excitation is the method of choice.

The solvent can affect the course of the reaction. If Wolff-Rearrangements are conducted in MeOH

as solvent, the occurrence of side products derived from an O-H insertion point to the intermediacy

of carbenes:

The course of the reaction and the migratory preferences can depend on the conditions (thermal,

photochemical, metal ion catalysis) of the reaction. Analysis of the product distribution helps to

determine different degrees of concertedness or the migratory aptitude of the group that rearranges.

If R is phenyl, the main product comes from the rearrangement, whereas the methyl group gives

more of the insertion side product.

The reactions of 2-diazo-1,3-diones also help to determine the migratory aptitude:

In a photolysis, methyl is preferred for rearrangement, whereas under thermolysis conditions the

phenyl substituent migrates preferentially. Hydrogen always exceeds the migratory aptitude of

phenyl groups. The alkoxy group in aryl or alkyl 2-diazoketocarboxylates never migrates.

More detailed explanations and additional examples can be found in a recent review by Kirmse

( Eur. J. Org. Chem. , 2002 , 2193-2256. DOI ) .

Beckmann Rearrangement

An acid-induced rearrangement of oximes to give amides.

This reaction is related to the Hofmann and Schmidt Reactions and the Curtius Rearrangement , in

that an electropositive nitrogen is formed that initiates an alkyl migration.

Mechanism of the Beckmann Rearrangement

Oximes generally have a high barrier to inversion, and accordingly this reaction is envisioned to

proceed by protonation of the oxime hydroxyl, followed by migration of the alkyl substituent

" trans " to nitrogen. The N-O bond is simultaneously cleaved with the expulsion of water, so that

formation of a free nitrene is avoided.

Benzilic Acid Rearrangement

1,2-Diketones undergo a rearrangement in the presence of strong base to yield α-hydroxycarboxylic

acids. The best yields are obtained when the subject diketones do not have enolizable protons.

The reaction of a cyclic diketone leads to an interesting ring contraction:

Ketoaldehydes do not react in the same manner, where a hydride shift is preferred (see Cannizzaro

Reaction )

Mechanism of Benzilic Acid Rearrangement

Benzoin Condensation

The Benzoin Condensation is a coupling reaction between two aldehydes that allows the

preparation of α-hydroxyketones. The first methods were only suitable for the conversion of

aromatic aldehydes.

Mechanism of Benzoin Condensation

Addition of the cyanide ion to create a cyanohydrin effects an umpolung of the normal carbonyl

charge affinity, and the electrophilic aldehyde carbon becomes nucleophilic after deprotonation: A

thiazolium salt may also be used as the catalyst in this reaction (see Stetter Reaction ).

A strong base is now able to deprotonate at the former carbonyl C-atom:

A second equivalent of aldehyde reacts with this carbanion; elimination of the catalyst regenerates

the carbonyl compound at the end of the reaction:

Acetoacetic-Ester Condensation

Claisen Condensation

The Claisen Condensation between esters containing α-hydrogens, promoted by a base such as

sodium ethoxide, affords β-ketoesters. The driving force is the formation of the stabilized anion of

the β-keto ester. If two different esters are used, an essentially statistical mixture of all four products

is generally obtained, and the preparation does not have high synthetic utility.

However, if one of the ester partners has enolizable α-hydrogens and the other does not (e.g.,

aromatic esters or carbonates), the mixed reaction (or crossed Claisen) can be synthetically useful.

If ketones or nitriles are used as the donor in this condensation reaction, a β-diketone or a β-

ketonitrile is obtained, respectively.

The use of stronger bases, e.g. sodium amide or sodium hydride instead of sodium ethoxide, often

increases the yield.

The intramolecular version is known as Dieckmann Condensation .

Mechanism of the Claisen Condensation

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