Demethylation

Source: Wikipedia, the free encyclopedia.

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

Dicamba, a widely used herbicide, biodegrades by demethylation to give 3,6-dichlorosalicylic acid, catalyzed by a dioxygenase enzyme.[3]

Demethylation is relevant to

oxidize N-methyl groups, which occur in histones, in lysine derivatives, and in some forms of DNA.[4]

R2N-CH3 + O → R2N-H + CH2O

One family of such oxidative enzymes is the

Alpha-ketoglutarate-dependent hydroxylases are also active for demethylation of DNA, operating by a similar stoichiometry.[6] These reactions, which proceed via hydroxylation, exploit the slightly weakened C-H bonds of methylamines and methyl ethers
.

Demethylation of some sterols are steps in the biosynthesis of testosterone and cholesterol. Methyl groups are lost as formate.[7]

Biomass processing

Methoxy groups heavily decorate the biopolymer lignin. Much interest has been shown in converting this abundant form of biomass into useful chemicals (aside from fuel). One step in such processing is demethylation. [8][9] The demethylation of vanillin, a derivative of lignin, requires 250 °C (482 °F) and strong base.[10] Pulp and paper industry]] digests lignin using aqueous sodium sulfide, which partially depolymerizes the lignin. Delignification is accompanied by extensive O-demethylation, yielding methanethiol, which is emitted by paper mills.[11]

In organic chemistry

Demethylation often refers to cleavage of

ethers, especially aryl ethers.[12]

Historically, aryl methyl ethers, including natural products such as

protonated aryl methyl ether (an arylmethyloxonium ion, pKa = –6.7 for aryl = Ph[16]). This is followed by SN2 attack of the arylmethyloxonium ion at the methyl group by either pyridine or chloride ion (depending on the substrate) to give the free phenol and, ultimately, N-methylpyridinium chloride, either directly or by subsequent methyl transfer from methyl chloride to pyridine.[15]

Another classical (but, again, harsh) method for the removal of the methyl group of an aryl methyl ether is to heat the ether in a solution of hydrogen bromide or hydrogen iodide sometimes also with acetic acid.[17] The cleavage of ethers by hydrobromic or hydroiodic acid proceeds by protonation of the ether, followed by displacement by bromide or iodide. A slightly milder set of conditions uses cyclohexyl iodide (CyI, 10.0 equiv) in N,N-dimethylformamide to generate a small amount of hydrogen iodide in situ.[18]

Boron tribromide, which can be used at room temperature or below, is a more specialized reagent for the demethylation of aryl methyl ethers. The mechanism of ether dealkylation proceeds via the initial reversible formation of a Lewis acid-base adduct between the strongly Lewis acidic BBr3 and the Lewis basic ether. This Lewis adduct can reversibly dissociate to give a dibromoboryl oxonium cation and Br–. Rupture of the ether linkage occurs through the subsequent nucleophilic attack on the oxonium species by Br– to yield an aryloxydibromoborane and methyl bromide. Upon completion of the reaction, the phenol is liberated along with boric acid (H3BO3) and hydrobromic acid (aq. HBr) upon hydrolysis of the dibromoborane derivative during aqueous workup.[19]

Stronger

thiolate salts like EtSNa.[21]

Aromatic methyl ethers, particularly those with an adjacent carbonyl group, can be regioselectively demethylated using magnesium iodide etherate.[22] An example of this being used is in the synthesis of the natural product Calphostin A,[23] as seen below.

Synthesis of Calphostin A by regioselective O-demethylation
Synthesis of Calphostin A by regioselective O-demethylation

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

A mixture of anethole, KOH, and alcohol was heated in an autoclave. Although the product of this reaction was the expected anol, a highly reactive dimerization product in the mother liquors called dianol was also discovered by Charles Dodds.

N-demethylation

N-demethylation of 3° amines is by the

Paxil from arecoline is an application of this reaction, as well as the synthesis of GSK-372,475
, for example.

The N-demethylation of imipramine gives desipramine.

See also

References

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  10. ^ Irwin A. Pearl (1949). "Protocatechulic Acid". Organic Syntheses. 29: 85; Collected Volumes, vol. 3, p. 745.
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  18. doi:10.1016/j.tetlet.2008.04.070
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  19. ^ J. F. W. McOmie, D. E. West (1969). "3,3'-Dihydroxybiphenyl". Organic Syntheses. 49: 13; Collected Volumes, vol. 5, p. 412.
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  21. doi:10.15227/orgsyn.053.0090
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  22. doi:10.1016/S0040-4039(99)01411-2
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