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

, 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 Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

to its homologue. It is named for the German chemists Fritz Arndt (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 ...

with

diazomethane Diazomethane is an organic chemical compound with the formula 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 ga ...

. 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 is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...

). A metal

catalyst Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

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 chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...

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. Like triethanolamine and the tetraethylammonium ion, it is often abbreviated TEA. It is a colourless volatile liquid with a strong fishy odor remini ...

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 an organic chemical compound with the formula 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 ga ...

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 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 acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distinct ...

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

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 α,β-unsaturated carbonyl compounds to give 1,3-dipolar cycloaddition products. An alternative to the Arndt–Eistert reaction is the Kowalski ester homologation, which also involves the generation of a carbene equivalent but avoids diazomethane.

Reaction mechanism

The acid chloride suffers attack by

with loss of HCl. The alpha-diazoketone (RC(O)CHN₂) product undergoes the metal-catalyzed Wolff rearrangement to form a

ketene In organic chemistry, a ketene is an organic compound of the form , where R and R' are two arbitrary valence (chemistry), monovalent functional group, chemical groups (or two separate Substituent, substitution sites in the same molecule). The na ...

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

Historical readings

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References

{{Organic reactions Rearrangement reactions Carbon-carbon bond forming reactions Homologation reactions Name reactions

Conditions

Variants

Reaction mechanism

Historical readings

See also

References