Demethylation

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Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule.[1][2] A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms.

In biochemistry[edit]

In biochemical systems, the process of demethylation is catalyzed by demethylases. These enzymes oxidize N-methyl groups, which occur in histones and some forms of DNA.

R2N-CH3 + O → R2N-H + CH2O

One such oxidative enzyme family is the cytochrome P450[3] Alpha-ketoglutarate-dependent nonheme enzymes are active for demethylation of DNA, operating by similar pathway.

In Organic chemistry[edit]

O-Desmethylation[edit]

Desmethylation, typically refers to cleavage of ethers, especially aryl ethers, although there is some exceptions, for instance cf. "desipramine".

Apparently, aryl ethers are pervasive in lignin-derived compounds.[citation needed]

The reaction typically requires harsh conditions or harsh reagents. For example, the methyl ether in vanillin can be removed by heating near 250 °C with strong base.[4] Stronger nucleophiles such as diorganophosphides (LiPPh2) also cleave aryl ethers under milder conditions.[5]

Boron tribromide is a classical reagent for the dealkylation of methyl arylethers. The mechanism of ether dealkylation proceeds via the formation of a complex between the boron center and the ether oxygen followed by the elimination of an alkyl bromide to yield a dibromo(organo)borane. The dibromo(organo)borane can then undergo hydrolysis to give the alcohol or phenol, boric acid, and hydrogen bromide as products.[6]

ROR + BBr3 → RO+(BBr3)R
RO+(BBr3)R → ROBBr2 + RBr
ROBBr2 + 3 H2O → ROH + B(OH)3 + 2 HBr

Methyl esters also are susceptible to demethylation, which is usually achieved by saponification. Highly specialized demethylations are abundant such as the Krapcho decarboxylation:

Krapcho reaction.svg

N-Demethylation[edit]

N-demethylation of 3° amines, is by the Von Braun reaction, which uses BrCN as the reagent to give the corresponding nor derivatives. The etymological meaning of the word nor is ″N ohne R″. A modern variation of the Von Braun rxn has been developed where BrCN has been superseded by ethyl chloroformate, respectively. Paxil prepared from arecoline is a good example of where this rxn has been applied, as well as GSK-372,475, for example.

References[edit]

  1. ^ Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. (2001). Organic Chemistry. Oxford, Oxfordshire: Oxford University Press. ISBN 0-19-850346-6. 
  2. ^ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 0-471-72091-7 
  3. ^ Roland Sigel; Sigel, Astrid; Sigel, Helmut (2007). The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences. New York: Wiley. ISBN 0-470-01672-8. 
  4. ^ Irwin A. Pearl (1949). "Protocatechulic Acid". Org. Synth. 29: 85. ; Coll. Vol. 3, p. 745 
  5. ^ Robert E. Ireland and David M. Walba (1977). "Demethylation of Methyl Aryl Ethers: 4-Ethoxy-3-hydroxybenzaldehyde". Org. Synth. 56: 44. ; Coll. Vol. 3, p. 745 
  6. ^ J. F. W. McOmie, D. E. West (1969). "3,3'-Dihydroxybiphenyl". Org. Synth. 49: 13. ; Coll. Vol. 5, p. 412 

See also[edit]