Demethylation

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.

The counterpart of demethylation is methylation.

In biochemistry

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

O-Desmethylation

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.

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:

N-Demethylation

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 A modern variation of the Von Braun rxn has been developed where BrCN has been superseded by ethyl chloroformate, respectively.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

  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

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