diazomethane

For safety and convenience diazomethane is always prepared as needed as a solution in ether and used as such. It converts carboxylic acids to methyl esters and phenols into their methyl ethers. The reaction is thought to proceed via proton transfer from carboxylic acid to diazomethane to give a methyldiazonium cation, which reacts with the carboxylate ion to give the methyl ester and nitrogen gas. Labeling studies indicate that the initial proton transfer is faster than the methyl transfer step.{{Cite journal|last1=van der Merwe|first1=K.J.|last2=Steyn|first2=P.S.|last3=Eggers|first3=S.H.|date=January 1964|title=A simple preparation of deuterium labelled O-methyl groups for mass spectrometry|url=https://linkinghub.elsevier.com/retrieve/pii/S0040403901893412|journal=Tetrahedron Letters|language=en|volume=5|issue=52|pages=3923–3925|doi=10.1016/S0040-4039(01)89341-2|via=|url-access=subscription}} Since proton transfer is required for the reaction to proceed, this reaction is selective for the more acidic carboxylic acids (pK_a ~ 5) and phenols (pK_a ~ 10) over aliphatic alcohols (pK_a ~ 15).{{Cite book|last=Clayden, Jonathan.|url=https://www.worldcat.org/oclc/761379371|title=Organic chemistry|date=2012|publisher=Oxford University Press|others=Greeves, Nick., Warren, Stuart G.|isbn=978-0-19-927029-3|edition=2nd|location=Oxford|pages=|oclc=761379371}}

File:Diazomethanemethylation.png

In more specialized applications, diazomethane and other diazoalkyl reagents are used in the Arndt–Eistert reaction and the Büchner–Curtius–Schlotterbeck reaction for homologation of various compounds.{{cite journal | title= Synthese von Ketonsäureäthern aus Aldehyden und Diazoessigäther | last1 = Buchner | first1 = E. | last2 = Curtius | first2 = Th. |journal=Berichte der Deutschen Chemischen Gesellschaft| year=1885| volume=18| issue = 2 |pages=2371–2377 | doi=10.1002/cber.188501802118| url = https://zenodo.org/record/1425403 }}{{cite journal | title=The conversion of aldehydes and ketones through diazomethane| author=Schlotterbeck, F. |journal=Berichte der Deutschen Chemischen Gesellschaft| year=1907| volume=40|pages=479–483| doi=10.1002/cber.19070400179| url=https://zenodo.org/record/1426219 }}

File:Buchner-Curtius-Schlotterbeck Reaction.svg

Diazomethane reacts with alcohols or phenols in presence of boron trifluoride (BF₃) to give methyl ethers.

Diazomethane is also frequently used as a carbene source. It readily takes part in 1,3-dipolar cycloadditions.

Image:Diazomethane preparation - Macro Diazald Kit.jpg

A wide variety of routes have been developed for the laboratory production of diazomethane.{{cite journal |last1=Horvath-Gerber |first1=Filip |last2=Ohlig |first2=Dominik |last3=Hii |first3=King Kuok Mimi |last4=Deadman |first4=Benjamin |last5=Attrill |first5=Robin P. |last6=Hellgardt |first6=Klaus |title=Liquizald─Thermally Stable N -Nitrosamine Precursor for Diazomethane |journal=Organic Process Research & Development |date=16 February 2024 |volume=28 |issue=2 |pages=597–608 |doi=10.1021/acs.oprd.3c00456|doi-access=free }} In general, the synthesis of these all involves the addition of methylamine to an electron-deficient species, before treatment with nitrite and mineral acid (nitrous acid) to form an N-methyl nitrosamide. Diazomethane is prepared by hydrolysis of an ethereal solution of these N-methyl nitrosamides with aqueous base. Examples include:

• N-nitroso-N-methylurea (NMU),{{cite journal |title=NITROSOMETHYLUREA |journal=Organic Syntheses |date=1935 |volume=15 |pages=48 |doi=10.15227/orgsyn.015.0048}}{{cite journal |title=DIAZOMETHANE |journal=Organic Syntheses |date=1935 |volume=15 |pages=3 |doi=10.15227/orgsyn.015.0003}} the original precursor first reported by Hans von Pechmann in 1894 and historically one of the most popular choices.{{cite journal |last1=Pechmann |first1=H. V. |title=Ueber Diazomethan |journal=Berichte der Deutschen Chemischen Gesellschaft |date=May 1894 |volume=27 |issue=2 |pages=1888–1891 |doi=10.1002/cber.189402702141}}{{cite journal |last1=v. Pechmann |first1=H. |title=Ueber Diazomethan |journal=Berichte der Deutschen Chemischen Gesellschaft |date=January 1895 |volume=28 |issue=1 |pages=855–861 |doi=10.1002/cber.189502801189}} Its popularity has slowly waned due to it being unstable at above 20 °C and somewhat shock-sensitive.
• N-Nitroso-β-methylaminoisobutyl methyl ketone (Liquizald), another early precursor which remains in use in the present day.{{cite journal |title=DIAZOMETHANE |journal=Organic Syntheses |date=1945 |volume=25 |pages=28 |doi=10.15227/orgsyn.025.0028}}
• N,N{{'}}-dimethyl-N,N{{'}}-dinitrosoterephthalamide (DMDMT){{cite journal |title=DIAZOMETHANE |journal=Organic Syntheses |date=1961 |volume=41 |pages=16 |doi=10.15227/orgsyn.041.0016}}
• N-methyl-N'-nitro-N-nitrosoguanidine (MNNG),{{Cite web|title=Synthese und Stoffwissen|url=https://organic-btc-ilmenau.jimdo.com/downloads-und-links/downloads/synthese-und-stoffwissen/|access-date=2020-11-02|website=organic-btc-ilmenaus Webseite!|language=de-DE}}{{cite journal|last=Reed|first=Donald E.|author2=James A. Moore|title=DIAZOMETHANE|journal=Organic Syntheses|date=1961|volume=41|page=16|doi=10.15227/orgsyn.041.0016}} used as both a biochemical tool and a diazomethane source.
• N-methyl-N-nitroso-p-toluenesulfonamide (Diazald),{{cite journal |title=p-TOLYLSULFONYLMETHYLNITROSAMIDE |journal=Organic Syntheses |date=1954 |volume=34 |pages=96 |doi=10.15227/orgsyn.034.0096}} one of the most popular modern precursors.

:File:Diazomethane Synthesis V.1.png

Diazomethane reacts with alkaline solutions of D₂O to give the deuterated derivative CD₂N₂.{{OrgSynth | author = P. G. Gassman | author2 = W. J. Greenlee | name-list-style=amp | title = Dideuterodiazomethane | collvol = 6 | collvolpages = 432 | prep = cv6p0432 | year = 1988}} This can be used for isotopic labeling studies.

The ease with which diazomethane explodes makes it too hazardous to handle in large quantities. Despite this, it can be used on an industrial scale using on-demand flow chemistry. In these processes the rate of production is matched by the rate of consumption, such that the amount of diazomethane present at any one time is very low.{{cite journal |last1=Yang |first1=Hongwei |last2=Martin |first2=Benjamin |last3=Schenkel |first3=Berthold |title=On-Demand Generation and Consumption of Diazomethane in Multistep Continuous Flow Systems |journal=Organic Process Research & Development |date=20 April 2018 |volume=22 |issue=4 |pages=446–456 |doi=10.1021/acs.oprd.7b00302}}

The concentration of CH₂N₂ can be determined in either of two convenient ways. It can be treated with an excess of benzoic acid in cold Et₂O. Unreacted benzoic acid is then back-titrated with standard NaOH. Alternatively, the concentration of CH₂N₂ in Et₂O can be determined spectrophotometrically at 410 nm where its extinction coefficient, ε, is 7.2.{{Citation needed|date=October 2010}}

The gas-phase concentration of diazomethane can be determined using photoacoustic spectroscopy.

Diazomethane is both isomeric and isoelectronic with the more stable cyanamide, but they do not interconvert.

Many substituted derivatives of diazomethane have been prepared:

• The very stable (CF₃)₂CN₂ (2-diazo-1,1,1,3,3,3-hexafluoropropane; b.p. 12–13 °C),{{cite journal |doi=10.15227/orgsyn.050.0006 |title=Bis(Trifluoromethyl)Diazomethane |journal=Organic Syntheses |date=1970 |volume=50 |page=6|first1=W. J. |last1=Middleton|first2=D. M. |last2=Gale }}
• Ph₂CN₂ (diazodiphenylmethane; m.p. 29–30 °C).{{OrgSynth | author = L. I. Smith | author2 = K. L. Howard | title = Diphenyldiazomethane" | collvol = 3 | collvolpages = 351 | prep = cv3p0351 | year = 1955}}
• (CH₃)₃SiCHN₂ (trimethylsilyldiazomethane), which is commercially available as a solution and is as effective as CH₂N₂ for methylation.{{OrgSynth | author1= T. Shioiri|author2=T. Aoyama|author3=S. Mori | title = Trimethylsilyldiazomethane | collvol = 8 | collvolpages = 612 | prep = cv8p0612}}
• PhC(H)N₂, a red liquid b.p.< 25 °C at 0.1 mmHg.{{OrgSynth | author = X. Creary | title = Tosylhydrazone Salt Pyrolyses: Phenydiazomethanes | collvol = 7 | collvolpages = 438 | year = 1990 | prep = cv7p0438}}

Diazomethane is toxic by inhalation or by contact with the skin or eyes (TLV 0.2 ppm). Symptoms include chest discomfort, headache, weakness and, in severe cases, collapse.Muir, GD (ed.) 1971, Hazards in the Chemical Laboratory, The Royal Institute of Chemistry, London. Symptoms may be delayed. Deaths from diazomethane poisoning have been reported. In one instance a laboratory worker consumed a hamburger near a fumehood where he was generating a large quantity of diazomethane, and died four days later from fulminating pneumonia.LeWinn, E.B. "Diazomethane Poisoning: Report of a fatal case with autopsy", The American Journal of the Medical Sciences, 1949, 218, 556-562. Like any other alkylating agent it is expected to be carcinogenic, but such concerns are overshadowed by its serious acute toxicity.

CH₂N₂ may explode in contact with sharp edges, such as ground-glass joints, even scratches in glassware.{{cite journal|last1=de Boer|first1=Th. J.|last2=Backer|first2=H. J.|title=DIAZOMETHANE|journal=Organic Syntheses|date=1956|volume=36|pages=16|doi=10.15227/orgsyn.036.0016}} Glassware should be inspected before use and preparation should take place behind a blast shield. Specialized kits to prepare diazomethane with flame-polished joints are commercially available.

The compound explodes when heated beyond 100 °C, exposed to intense light, alkali metals, or calcium sulfate. Use of a blast shield is highly recommended while using this compound.

Proof-of-concept work has been done with microfluidics, in which continuous point-of-use synthesis from N-methyl-N-nitrosourea and 0.93 M potassium hydroxide in water was followed by point-of-use conversion with benzoic acid, resulting in a 65% yield of the methyl benzoate ester within seconds at temperatures ranging from 0 to 50 °C. The yield was better than under capillary conditions; the microfluidics were credited with "suppression of hot spots, low holdup, isothermal conditions, and intensive mixing."{{cite book|url=https://books.google.com/books?id=yUrdAAAAQBAJ&pg=SA6-PA15|title=Microreactors in Preparative Chemistry: Practical Aspects in Bioprocessing, Nanotechnology, Catalysis and more|publisher=Wiley|date=2013-09-13|author=Wladimir Reschetilowski|page=6–15|isbn=9783527652914}}

The stable compound cyanamide, whose minor tautomer is carbodiimide, is an isomer of diazomethane. Less stable but still isolable isomers of diazomethane include the cyclic 3H-diazirine and isocyanoamine (isodiazomethane).{{Cite journal|last=Anselme|first=J.-P.|date=1977-05-01|title=Isodiazomethane revisited. N-aminoisonitriles|journal=Journal of Chemical Education|volume=54|issue=5|pages=296|doi=10.1021/ed054p296|bibcode=1977JChEd..54..296A|issn=0021-9584}}{{Cite journal|last=Anselme|first=J. P.|date=1966-11-01|title=The chemistry of isodiazomethane|journal=Journal of Chemical Education|volume=43|issue=11|pages=596|doi=10.1021/ed043p596|bibcode=1966JChEd..43..596A|issn=0021-9584}} In addition, the parent nitrilimine has been observed under matrix isolation conditions.{{Cite book|title=Comprehensive organic functional group transformations II|date=2005|publisher=Elsevier|others=Katritzky, Alan R., Taylor, Richard J. K.|isbn=9780080523477|edition=1st|location=Amsterdam|oclc=213375246}}

File:Diazomethaneisomers.png

{{Reflist}}

{{Commons category}}

• [http://www.inchem.org/documents/icsc/icsc/eics1256.htm MSDS diazomethane]
• [https://www.cdc.gov/niosh/npg/npgd0182.html CDC - NIOSH Pocket Guide to Chemical Hazards]
• [https://web.archive.org/web/20110606083207/http://www.sigmaaldrich.com/etc/medialib/docs/Aldrich/Bulletin/al_techbull_al180.pdf Sigmaaldrich technical bulletin] (PDF)
• [http://www.sigmaaldrich.com/chemistry/chemical-synthesis/technology-spotlights/diazald.html Sigma-Aldrich] diazomethane applications and commercial availability of (Diazald) precursor
• [http://littlemsandsailing.wordpress.com/2011/05/01/identification-of-artifacts-in-diazoalkane-derivatization-reactions/ Identification of Artifacts (By-Products) in Diazomethane and Trimethylsilyldiazomethane Reactions]
• [https://i.pinimg.com/originals/78/82/f6/7882f61f013e3495cb7931ed8ee603e7.jpg A flask of diazomethane solution, photographed]

{{Nitrogen compounds}}

Category:Diazo compounds

Category:Methylating agents

Category:IARC Group 3 carcinogens

Category:Reagents for organic chemistry

Category:Explosive chemicals

Category:1894 in science

Category:Gases with color

Category:Explosive gases

Category:Organic compounds with 1 carbon atom