Demethylation is the chemical process resulting in the removal of amethyl 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 ismethylation.
Demethylation is relevant toepigenetics. Demethylation of DNA iscatalyzed bydemethylases. These enzymesoxidize N-methyl groups, which occur inhistones, in lysine derivatives, and in some forms of DNA.[4]
One family of such oxidative enzymes is thecytochrome P450.[5]Alpha-ketoglutarate-dependent hydroxylases are also active for demethylation of DNA, operating by a similar stoichiometry.[6] These reactions, which proceed viahydroxylation, exploit the slightly weakenedC-H bonds ofmethylamines andmethyl ethers.
Demethylation of somesterols are steps in the biosynthesis oftestosterone andcholesterol. Methyl groups are lost asformate.[7]
Methoxy groups heavily decorate the biopolymerlignin. 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 ofvanillin, a derivative of lignin, requires 250 °C (482 °F) and strong base.[10]Pulp and paper industry digests lignin using aqueoussodium sulfide, which partially depolymerizes the lignin. Delignification is accompanied by extensive O-demethylation, yieldingmethanethiol, which is emitted bypaper mills as an air pollutant.[11]
Demethylation often refers to cleavage ofethers, especially aryl ethers.[12]
Historically, aryl methyl ethers, including natural products such ascodeine (O-methylmorphine), have been demethylated by heating the substance in molten pyridinehydrochloride (melting point 144 °C (291 °F)) at 180 to 220 °C (356 to 428 °F), sometimes with excesshydrogen chloride, in a process known as theZeisel–Prey ether cleavage.[13][14] Quantitative analysis for aromatic methyl ethers can be performed byargentometric determination of theN-methylpyridinium chloride formed.[15] The mechanism of this reaction starts with proton transfer frompyridinium 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 theprotonated aryl methyl ether (an arylmethyloxonium ion, pKa = –6.7 for aryl = Ph[16]). This is followed bySN2 attack of the arylmethyloxonium ion at the methyl group by eitherpyridine 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 ofhydrogen bromide orhydrogen iodide sometimes also withacetic acid.[17] The cleavage of ethers by hydrobromic or hydroiodic acid proceeds by protonation of the ether, followed by displacement bybromide oriodide. A slightly milder set of conditions uses cyclohexyl iodide (CyI, 10.0 equiv) inN,N-dimethylformamide to generate a small amount of hydrogen iodidein 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 aLewis 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) uponhydrolysis of the dibromoborane derivative during aqueousworkup.[19]
Strongernucleophiles such asdiorganophosphides (LiPPh2) also cleave aryl ethers, sometimes under mild conditions.[20] Other strong nucleophiles that have been employed includethiolate salts like EtSNa.[21]
Aromatic methyl ethers, particularly those with an adjacent carbonyl group, can be regioselectively demethylated usingmagnesium iodide etherate.[22] An example of this being used is in the synthesis of the natural product Calphostin A,[23] as seen below.
Methyl esters also are susceptible to demethylation, which is usually achieved bysaponification. Highly specialized demethylations are abundant, such as theKrapcho decarboxylation:
A mixture ofanethole, KOH, and alcohol was heated in an autoclave. Although the product of this reaction was the expectedanol, a highly reactive dimerization product in the mother liquors calleddianol was also discovered byCharles Dodds.
N-demethylation of 3° amines is by thevon Braun reaction, which usesBrCN as thereagent to give the correspondingnor- derivatives. A modern variation of the von Braun reaction was developed, where BrCN was superseded byethyl chloroformate. The preparation ofPaxil fromarecoline is an application of this reaction, as well as the synthesis ofGSK-372,475, for example.
TheN-demethylation ofimipramine givesdesipramine.
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