- 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 thehomologous series . For example the reaction ofaldehyde s andketone s withdiazomethane ormethoxymethylenetriphenylphosphine effectively inserts amethylene (-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 analdose molecule is elongated through a three-step process consisting of:
*#Nucleophillic addition of cyanide to the carbonyl to form acyanohydrin
*# Hydrolysis to form alactone
*# Reduction to form the homologous aldose
*Wittig reaction of an aldehyde withmethoxymethylenetriphenylphosphine , 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 anynolate 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 aliphaticcarboxylic 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 ACIDJ. Biol. Chem. , Mar 1946; 162: 549 - 554 [http://www.jbc.org/cgi/reprint/162/3/549 Link] ] . The original publication concerns the conversion ofbile acid in a series of reactions:acid chloride (2) formation withthionyl chloride ,diazoketone formation (3) withdiazomethane , chloromethyl ketone formation (4) withhydrochloric acid ,organic reduction of chlorine to methylketone (5),ketone halogenation to 6,elimination reaction withpyridine toenone 7 and finally oxidation withchromium trioxide to "bisnorcholanic acid" 8. :* In the Hooker reaction (1936) an alkyl chain in a certain
naphthoquinone (phenomenon first observed in the compoundlapachol ) is reduced by onemethylene unit ascarbon dioxide in eachpotassium permanganate oxidation ["On the Oxidation of 2-Hydroxy-1,4-naphthoquinone Derivatives with Alkaline Potassium Permanganate" Samuel C. HookerJ. 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 SteyermarkJ. Am. Chem. Soc. 1936; 58(7); pp 1179 - 1181; DOI|10.1021/ja01298a031] .::Mechanistically oxidation causes ring-cleavage at the alkene group, extrusion ofcarbon dioxide indecarboxylation with subsequent ring-closure.See also
*
Homologous series References
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