organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...

, the Arndt–Eistert reaction is the conversion of a

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

to its homologue. Named for the German chemists

Fritz Arndt Fritz Georg Arndt (6 July 1885 – 8 December 1969) was a German chemist recognised for his contributions to synthetic methodology, who together with Bernd Eistert discovered the Arndt-Eistert synthesis. Life Fritz Arndt was born on 6 July ...

(1885–1969) and Bernd Eistert (1902–1978), the method entails treating an

acid chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...

s with

diazomethane Diazomethane is the chemical compound CH2N2, discovered by German chemist Hans von Pechmann in 1894. It is the simplest diazo compound. In the pure form at room temperature, it is an extremely sensitive explosive yellow gas; thus, it is almost u ...

. It is a popular method of producing β-amino acids from α-amino acids.

Conditions

Aside from the acid chloride substrate, three reagents are required: diazomethane, water, and a metal catalyst. Each has been well investigated. The diazomethane is required in excess so as to react with the HCl formed previously. Not taking

in excess results in HCl reacting with the diazoketone to form chloromethyl ketone and N₂. Mild conditions allow this reaction to take place while not affecting complex or reducible groups in the reactant-acid. The reaction requires the presence of a

nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

(

water Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as a ...

). A metal

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

is required. Usually Ag₂O is chosen but other metals and even light effect the reaction. : A-EpathRCOCl

Variants

The preparation of the beta-amino acid from

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

illustrates the Arndt–Eistert synthesis carried out with the Newman–Beal modification, which involves the inclusion of

triethylamine Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine or tetraethylammonium, for which TEA ...

in the diazomethane solution. Either

or a second equivalent of diazomethane will scavenge HCl, avoiding the formation of α-chloromethylketone side-products.

Diazomethane Diazomethane is the chemical compound CH2N2, discovered by German chemist Hans von Pechmann in 1894. It is the simplest diazo compound. In the pure form at room temperature, it is an extremely sensitive explosive yellow gas; thus, it is almost u ...

is the traditional reagent, but analogues can also be applied. Diazomethane is toxic and potentially violently explosive, which has led to safer alternative procedures, For example, diazo(trimethylsilyl)methane has been demonstrated.

Acid anhydrides An organic acid anhydride is an acid anhydride that is an organic compound. An acid anhydride is a compound that has two acyl groups bonded to the same oxygen atom. A common type of organic acid anhydride is a carboxylic anhydride, where the pa ...

can be used in place of acid chloride. The reaction yields a 1:1 mixture of the homologated acid and the corresponding

methyl ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are fa ...

. This method can also be used with primary diazoalkanes, to produce secondary α-diazo ketones. However, there are many limitations. Primary diazoalkanes undergo

azo coupling In organic chemistry, an azo coupling is an organic reaction between a diazonium compound () and another aromatic compound that produces an azo compound (). In this electrophilic aromatic substitution reaction, the aryldiazonium cation is the ...

to form azines; thus the reaction conditions must be altered such that acid chloride is added to a solution of diazoalkane and triethylamine at low temperature. In addition, primary diazoalkanes are very reactive, incompatible with acidic functionalities, and will react with activated alkenes including unsaturated carbonyls to give 1,3-dipolar cycloaddition products. An alternative to the Arndt–Eistert reaction is the

Kowalski ester homologation The Kowalski ester homologation is a chemical reaction for the homologation of esters. This reaction was designed as a safer alternative to the Arndt–Eistert synthesis, avoiding the need for diazomethane. The Kowalski reaction is named after ...

, which also involves the generation of a carbene equivalent but avoids diazomethane.

Reaction mechanism

The acid chloride suffers attack by

with loss of

HCl HCL may refer to: Science and medicine * Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia * Harvard Cyclotron Laboratory, from 1961 to 2002, a proton accelerator used for research and development * Hollow-cathode lamp, a spe ...

. The alpha-diazoketone (RC(O)CHN₂) product undergoes the metal-catalyzed

Wolff rearrangement The Wolff rearrangement is a reaction in organic chemistry in which an α-diazocarbonyl compound is converted into a ketene by loss of dinitrogen with accompanying 1,2-rearrangement. The Wolff rearrangement yields a ketene as an intermediate produ ...

to form a

ketene In organic chemistry, a ketene is an organic compound of the form , where R and R' are two arbitrary monovalent chemical groups (or two separate substitution sites in the same molecule). The name may also refer to the specific compound etheno ...

, which hydrates to the acid. The rearrangement leaves untouched the stereochemistry at the carbon alpha to the acid chloride. :

Historical readings

* *

References

{{DEFAULTSORT:Arndt-Eistert reaction Rearrangement reactions Carbon-carbon bond forming reactions Name reactions Homologation reactions

Conditions

Variants

Reaction mechanism

Historical readings

See also

References