Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. 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.
- R2N-CH3 + O → R2N-H + CH2O
One such oxidative enzyme family is the cytochrome P450. Alpha-ketoglutarate-dependent hydroxylases are active for demethylation of DNA, operating by similar pathway. These reactions exploit the weak C-H bond adjacent to amines.
In organic chemistry
Demethylation typically refers to cleavage of ethers, especially aryl ethers, although there are some exceptions, for instance cf. "desipramine".
Aryl methyl ethers are pervasive in lignin and many derived compounds. The demethylation of these materials has been the subject of much effort. 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. Stronger nucleophiles such as diorganophosphides (LiPPh2) also cleave aryl ethers under milder conditions. Other strong nucleophiles that have been employed include thiolates salts like EtSNa.
Acidic conditions can also be used. Historically, aryl methyl ethers, including natural products such as codeine (O-methylmorphine), have been demethylated by heating the substance in molten pyridine hydrochloride (m.p. 144 °C) at 180 to 220 °C, sometimes with excess hydrogen chloride, in a process known as the Zeisel–Prey ether cleavage. Quantitative analysis for aromatic methyl ethers can be performed by argentometric determination of the N-methylpyridinium chloride formed. The mechanism of this reaction starts with proton transfer from pyridinium ion to the aryl methyl ether, a highly unfavorable step (K < 10–11) that accounts for the harsh conditions required, given the much weaker acidity of pyridinium (pKa = 5.2) compared to the protonated aryl methyl ether (an arylmethyloxonium ion, pKa = –6.7 for aryl = Ph). 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.
Another classical (but again, harsh) method for the removal of the methyl group of an aryl methyl ether is to heat the ether to reflux in a solution of hydrogen bromide or hydrogen iodide in acetic acid (b.p. 118 °C) or concentrated hydrobromic or hydroiodic acid. The cleavage of ethers by hydrobromic or hydroiodic acid proceeds by a very similar mechanism, in which the highly acidic HBr or HI serves to protonate the ether, followed by displacement by bromide or iodide, both of which are excellent nucleophiles. 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. 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.
N-demethylation of 3° amines is by the von Braun reaction, which uses BrCN as the reagent to give the corresponding nor- derivatives. A modern variation of the Von Braun reaction was developed where BrCN was superseded by ethyl chloroformate. The preparation of Paxil from arecoline is an application of this reaction, as well as the synthesis of GSK-372,475, for example.
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