Editing Demethylation

{{Short description|Process of removing one or more methyl groups from a molecule}}
'''Demethylation''' is the chemical process resulting in the removal of a [[methyl group]] (CH<sub>3</sub>) from a molecule.<ref name="Clayden1st">{{cite book |last1=Clayden |first1=J. |url=https://archive.org/details/organicchemistry00clay_0 |title=Organic Chemistry |last2=Greeves |first2=N. |last3=Warren |first3=S. |last4=Wothers |first4=P. |publisher=[[Oxford University Press]] |year=2001 |isbn=978-0-19-850346-0 |location=Oxford, Oxfordshire |url-access=registration}}</ref><ref name="March6th">{{March6th}}</ref> 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 ==
:[[File:DicambaDeMeth.svg|thumb|left|Dicamba, a widely used herbicide, biodegrades by demethylation to give 3,6-[[dichlorosalicylic acid]], catalyzed by a [[dioxygenase]] [[enzyme]].<ref>{{cite journal |doi=10.1016/j.jmb.2009.07.021 |title=Crystal Structure of Dicamba Monooxygenase: A Rieske Nonheme Oxygenase that Catalyzes Oxidative Demethylation |date=2009 |last1=Dumitru |first1=Razvan |last2=Jiang |first2=Wen Zhi |last3=Weeks |first3=Donald P. |last4=Wilson |first4=Mark A. |journal=Journal of Molecular Biology |volume=392 |issue=2 |pages=498–510 |pmid=19616011 |pmc=3109874 }}</ref> |422px]]

Demethylation is relevant to [[epigenetic]]s.  Demethylation of DNA is [[catalyst|catalyzed]] by [[demethylase]]s.  These enzymes [[oxidize]] N-methyl groups, which occur in [[histone]]s, in lysine derivatives, and in some forms of DNA.<ref name="Ped">{{cite journal | vauthors = Pedersen MT, Helin K | title = Histone demethylases in development and disease | journal = Trends in Cell Biology | volume = 20 | issue = 11 | pages = 662–71 | date = Nov 2010 | pmid = 20863703 | doi = 10.1016/j.tcb.2010.08.011 }}</ref>  
:R<sub>2</sub>N-CH<sub>3</sub>  +  O   →   R<sub>2</sub>N-H   +  CH<sub>2</sub>O
One family of such oxidative enzymes is the [[cytochrome P450]].<ref name="isbn0-470-01672-8">{{cite book |author1=Roland Sigel |author2=Sigel, Astrid |author3=Sigel, Helmut | title = The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences | publisher = Wiley | location = New York | year = 2007 | isbn = 978-0-470-01672-5 }}</ref> [[Alpha-ketoglutarate-dependent hydroxylase]]s are also active for demethylation of DNA, operating by a similar stoichiometry.<ref name="pmid24153300">{{cite journal |vauthors=Kohli RM, Zhang Y |title=TET enzymes, TDG and the dynamics of DNA demethylation |journal=Nature |volume=502 |issue=7472 |pages=472–9 |date=October 2013 |pmid=24153300 |pmc=4046508 |doi=10.1038/nature12750 |bibcode=2013Natur.502..472K }}</ref>  These reactions, which proceed via [[hydroxylation]], exploit the slightly weakened [[Carbon–hydrogen bond|C-H bond]]s of [[methylamine]]s and [[methyl ether]]s.

Demethylation of some [[sterol]]s are steps in the biosynthesis of [[testosterone]] and [[cholesterol]].  Methyl groups are lost as [[formate]].<ref>{{cite journal |doi=10.1016/j.molmet.2019.05.012|title=Formate Metabolism in Health and Disease |year=2020 |last1=Pietzke |first1=Matthias |last2=Meiser |first2=Johannes |last3=Vazquez |first3=Alexei |journal=Molecular Metabolism |volume=33 |pages=23–37 |pmid=31402327 |pmc=7056922 }}</ref>

==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.
<ref>{{cite journal |doi=10.1016/j.checat.2022.07.005 |title=Expanding the repertoire of Rieske oxygenases for O-demethylations |date=2022 |last1=Schmidt |first1=Sandy |journal=Chem Catalysis |volume=2 |issue=8 |pages=1843–1845 }}</ref><ref name="boerjan">{{cite journal |author1=W. Boerjan |author2=J. Ralph |author3=M. Baucher |date=June 2003 |title=Lignin biosynthesis |journal=[[Annu. Rev. Plant Biol.]] |volume=54 |issue=1 |pages=519–549 |doi=10.1146/annurev.arplant.54.031902.134938 |pmid=14503002|url=https://biblio.ugent.be/publication/211742/file/4144786 |url-access=subscription }}</ref>  The demethylation of [[vanillin]], a derivative of lignin, requires {{Convert|250|C|F|abbr=|sp=us}} and strong base.<ref>{{OrgSynth |author=Irwin A. Pearl |year=1949 |title=Protocatechulic Acid |volume=29 |pages=85 |collvol=3 |collvolpages=745 |prep=CV3P0745}}</ref> [[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 mill]]s as an air pollutant.<ref>{{cite journal |doi=10.1080/00022470.1962.10468107 |title=Odor ''and'' Fallout Control ''in a Kraft Pulp Mill'' |date=1962 |last1=Hansen |first1=G. A. |journal=Journal of the Air Pollution Control Association |volume=12 |issue=9 |pages=409–436 |pmid=13904415 }}</ref>

==In organic chemistry==
Demethylation often refers to cleavage of [[ethers]], especially aryl ethers.<ref>{{cite journal |doi=10.1016/j.tet.2005.05.041|title=Recent Advances in Ether Dealkylation|year=2005|last1=Weissman|first1=Steven A.|last2=Zewge|first2=Daniel|journal=Tetrahedron|volume=61|issue=33|pages=7833–7863}}</ref>

Historically, aryl methyl ethers, including natural products such as [[codeine]] (''O''-methylmorphine), have been demethylated by heating the substance in molten pyridine [[hydrochloride]] (melting point {{Convert|144|C|F|abbr=|sp=us}}) at {{Convert|180 to 220|C|F|abbr=|sp=us}}, sometimes with excess [[hydrogen chloride]], in a process known as the ''Zeisel–Prey ether cleavage''.<ref>{{Cite journal |last1=Lawson |first1=J. A. |last2=DeGraw |first2=J. I. |date=1977 |title=An improved method for O-demethylation of codeine |journal=[[Journal of Medicinal Chemistry]] |volume=20 |issue=1 |pages=165–166 |doi=10.1021/jm00211a037 |issn=0022-2623 |pmid=833817}}</ref><ref>{{Cite book |last1=Hassner |first1=Alfred |title=Organic syntheses based on name reactions |last2=Stumer |first2=C. |date=2002 |publisher=[[Pergamon]] |isbn=9780080513348 |edition=2nd |location=Amsterdam |oclc=190810761}}</ref>  Quantitative analysis for aromatic methyl ethers can be performed by [[Argentometry|argentometric]] determination of the [[N-methylpyridinium chloride|''N''-methylpyridinium chloride]] formed.<ref name=":0">{{Cite journal |last=Burwell |first=Robert L. |date=1954-08-01 |title=The Cleavage of Ethers |journal=[[Chemical Reviews]] |volume=54 |issue=4 |pages=615–685 |doi=10.1021/cr60170a003 |issn=0009-2665}}</ref>  The mechanism of this reaction starts with proton transfer from [[pyridinium]] ion to the aryl methyl ether, a highly unfavorable step (''K'' < 10<sup>−11</sup>) that accounts for the harsh conditions required, given the much weaker acidity of pyridinium ([[PKa|p''K''<sub>a</sub>]] = 5.2) compared to the [[protonated]] aryl methyl ether (an arylmethyloxonium ion, p''K''<sub>a</sub> = –6.7 for aryl = Ph<ref>{{Cite book |title=Organic chemistry : structure and function |last1=Vollhardt|first1= Peter|last2=Schore |first2=Neil |isbn=9781464120275|edition=Seventh |location=New York, NY|oclc=866584251|date=2014-01-01}}</ref>).  This is followed by [[SN2 reaction|S<sub>N</sub>2 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.<ref name=":0" />[[File:Prey ether cleavage.png|center|frameless|400x400px]]

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]].<ref>{{Cite book |last1=Streitwieser |first1=Andrew |title=Introduction to organic chemistry |last2=Heathcock |first2=Clayton H. |last3=Kosower |first3=Edward M. |date=1992 |publisher=[[Prentice Hall]] |isbn=978-0139738500 |edition=4th |location=Upper Saddle River, N.J. |oclc=52836313}}</ref> 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 [[Dimethylformamide|''N'',''N''-dimethylformamide]] to generate a small amount of hydrogen iodide ''[[in situ]]''.<ref>{{Cite journal |last1=Zuo |first1=Li |last2=Yao |first2=Shanyan |last3=Wang |first3=Wei |last4=Duan |first4=Wenhu |date=June 2008 |title=An efficient method for demethylation of aryl methyl ethers |journal=[[Tetrahedron Letters]] |language=en |volume=49 |issue=25 |pages=4054–4056 |doi=10.1016/j.tetlet.2008.04.070}}</ref>  

[[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 acids and bases|Lewis acid-base]] adduct between the strongly Lewis acidic BBr<sub>3</sub> and the Lewis basic ether.   This Lewis adduct can reversibly dissociate to give a dibromoboryl oxonium cation and Br<sup>–</sup>.  Rupture of the ether linkage occurs through the subsequent nucleophilic attack on the oxonium species by Br<sup>–</sup> to yield an aryloxydibromoborane and methyl bromide.  Upon completion of the reaction, the phenol is liberated along with boric acid (H<sub>3</sub>BO<sub>3</sub>) and hydrobromic acid (aq. HBr) upon [[hydrolysis]] of the dibromoborane derivative during aqueous [[Work-up|workup]].<ref name=McOmie>{{OrgSynth|author= J. F. W. McOmie, D. E. West |year=1969|title=3,3'-Dihydroxybiphenyl|volume=49|pages=13|collvol=5|collvolpages=412|prep=CV5P0412}}</ref>
[[File:BBr3demethylation.png|center|frameless|350x350px]]

Stronger [[nucleophiles]] such as [[Phosphide#Organic phosphides|diorganophosphides]] (LiPPh<sub>2</sub>) also cleave aryl ethers, sometimes under mild conditions.<ref>{{OrgSynth|author=Robert E. Ireland |title=Demethylation of methyl aryl ethers |author2=David M. Walba |year=1977 |volume=56 |pages=44 |doi=10.1002/0471264180.os056.11|isbn=978-0471264224 |prep=CV6P0567 }}</ref>  Other strong nucleophiles that have been employed include [[Thiolate|thiolate salts]] like EtSNa.<ref>{{OrgSynth|doi=10.15227/orgsyn.053.0090 |title=Orcinol Monomethyl Ether |date=1973 |volume=53 |page=90|first1=R. N.|last1=Mirrington|first2=G. I.|last2=Feutrill|prep=CV6P0859}}</ref>

Aromatic methyl ethers, particularly those with an adjacent carbonyl group, can be [[Regioselectivity | regioselectively]] demethylated using [[magnesium iodide]] etherate.<ref>{{cite journal |last1=Yamaguchi |first1=Seiji |last2=Nedachi |first2=Masahiro |last3=Yokoyama |first3=Hajime |last4=Hirai |first4=Yoshiro |title=Regioselective demethylation of 2,6-dimethoxybenzaldehydes with magnesium iodide etherate |journal=Tetrahedron Letters |date=October 1999 |volume=40 |issue=41 |pages=7363–7365 |doi=10.1016/S0040-4039(99)01411-2}}</ref> An example of this being used is in the synthesis of the natural product [[Calphostin | Calphostin A]],<ref>{{cite journal |last1=Merlic |first1=Craig A. |last2=Aldrich |first2=Courtney C. |last3=Albaneze-Walker |first3=Jennifer |last4=Saghatelian |first4=Alan |title=Carbene Complexes in the Synthesis of Complex Natural Products: Total Synthesis of the Calphostins |journal=Journal of the American Chemical Society |date=1 April 2000 |volume=122 |issue=13 |pages=3224–3225 |doi=10.1021/ja994313+|pmid=23335811 |pmc=3548573 }}</ref> as seen below.
[[File:CalphostinA_synth_v1.svg|center|420px|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]]:

:[[File:Krapcho reaction.svg|400px]]
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 [[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 [[NS-2359|GSK-372,475]], for example.

The ''N''-demethylation of [[imipramine]] gives [[desipramine]].

==See also==
* [[Methylation]], the addition of a [[methyl group]] to a [[Substrate (chemistry)|substrate]]

== References ==
{{Reflist|30em}}

[[Category:Gene expression]]
[[Category:Organic reactions]]