Homologation reaction

A homologation reaction, also known as homologization, is any chemical reaction that effects an overall increase of the carbon skeleton of a saturated reactant molecule. ["Encyclopedia of Inorganic Chemistry" DOI|10.1002/0470862106.id396] The reactants undergo a homologation converting them into the next member of the homologous series. For example the reaction of aldehydes and ketones with diazomethane or methoxymethylenetriphenylphosphine effectively inserts a methylene (-CH₂-) unit in the hydrocarbon chain and the reaction product is the next homologue.

Examples of homologation reactions include:

* Seyferth-Gilbert homologation
* Displacement of a halide by a cyanide group, which can be reduced to an amine, see: Kolbe nitrile synthesis
* Kiliani-Fischer synthesis, where an aldose molecule is elongated through a three-step process consisting of:
*# Nucleophillic addition of cyanide to the carbonyl to form a cyanohydrin
*# Hydrolysis to form a lactone
*# Reduction to form the homologous aldose
* Wittig reaction of an aldehyde with methoxymethylenetriphenylphosphine, which produces a homologous aldehyde.
* Arndt-Eistert synthesis is a series of chemical reactions designed to convert a carboxylic acid to a higher carboxylic acid homologue (ie. contains one additional carbon atom)
* Kowalski ester homologation, an alternative to the Arndt-Eistert synthesis. Has been used to convert β-amino esters from α-amino esters through an ynolate intermediate. [cite journal | author = D. Gray, C. Concellon and T. Gallagher | title = Kowalski Ester Homologation. Application to the Synthesis of β-Amino Esters | year = 2004 | journal = J. Org. Chem. | volume = 69 | issue = 14 | pages = 4849–4851 | doi = 10.1021/jo049562h]

Some reactions increase the chain length by more than one unit. For example, the following are considered two-carbon homologation reactions:

* Nucleophilic addition to ethylene oxide, resulting in a ring-opening and producing a primary alcohol with two extra carbons.
* Malonic ester synthesis, which produces a carboxylic acid with two extra carbons.

Chain reduction

Likewise the chain length can also be reduced:
* In the Gallagher-Hollander Degradation (1946) pyruvic acid is removed from a linear aliphatic carboxylic acid yielding a new acid with 2 carbon atoms less [Vincent P. Hollander and T. F. GallagherPARTIAL SYNTHESIS OF COMPOUNDS RELATED TO ADRENAL CORTICAL HORMONES. VII. DEGRADATION OF THE SIDE CHAIN OF CHOLANIC ACID J. Biol. Chem., Mar 1946; 162: 549 - 554 [http://www.jbc.org/cgi/reprint/162/3/549 Link] ] . The original publication concerns the conversion of bile acid in a series of reactions: acid chloride (2) formation with thionyl chloride, diazoketone formation (3) with diazomethane, chloromethyl ketone formation (4) with hydrochloric acid, organic reduction of chlorine to methylketone (5), ketone halogenation to 6, elimination reaction with pyridine to enone 7 and finally oxidation with chromium trioxide to "bisnorcholanic acid" 8. :

* In the Hooker reaction (1936) an alkyl chain in a certain naphthoquinone (phenomenon first observed in the compound lapachol) is reduced by one methylene unit as carbon dioxide in each potassium permanganate oxidation ["On the Oxidation of 2-Hydroxy-1,4-naphthoquinone Derivatives with Alkaline Potassium Permanganate" Samuel C. Hooker J. Am. Chem. Soc. 1936; 58(7); 1174-1179. DOI|10.1021/ja01298a030] ["On the Oxidation of 2-Hydroxy-1,4-naphthoquinone Derivatives with Alkaline Potassium Permanganate. Part II. Compounds with Unsaturated Side" Chains Samuel C. Hooker and Al Steyermark J. Am. Chem. Soc. 1936; 58(7); pp 1179 - 1181; DOI|10.1021/ja01298a031] .::Mechanistically oxidation causes ring-cleavage at the alkene group, extrusion of carbon dioxide in decarboxylation with subsequent ring-closure.

See also

* Homologous series

References