Diazo#Occurrence in nature

The electronic structure of diazo compounds is characterized by π electron density delocalized over the α-carbon and two nitrogen atoms, along with an orthogonal π system with electron density delocalized over only the terminal nitrogen atoms. Because all octet rule-satisfying resonance forms of diazo compounds have formal charges, they are members of a class of compounds known as 1,3-dipoles. Some of the most stable diazo compounds are α-diazo-β-diketones and α-diazo-β-diesters, in which the electron density is further delocalized into an electron-withdrawing carbonyl group. In contrast, most diazoalkanes without electron-withdrawing substituents, including diazomethane itself, are explosive. A commercially relevant diazo compound is ethyl diazoacetate (N₂CHCOOEt). A group of isomeric compounds with only few similar properties are the diazirines, where the carbon and two nitrogens are linked as a ring.

Four resonance structures can be drawn:F.A. Carey R.J. Sundberg Advanced Organic Chemistry, 2nd Edition

:Diazo resonance structures

Compounds with the diazo moiety should be distinguished from diazonium compounds, which have the same terminal azo group but bear an overall positive charge, and azo compounds in which the azo group bridges two organic substituents.

Diazo compounds were first produced by Peter Griess who had discovered a versatile new chemical reaction, as detailed in his 1858 paper "Preliminary notice on the influence of nitrous acid on aminonitro- and aminodinitrophenol."Trevor I. Williams, 'Griess, (Johann) Peter (1829–1888)', Oxford Dictionary of National Biography, Oxford University Press, 2004Peter Griess (1858) [http://babel.hathitrust.org/cgi/pt?id=njp.32101044011037;view=1up;seq=541 "Vorläufige Notiz über die Einwirkung von salpetriger Säure auf Amidinitro- und Aminitrophenylsäure,"] (Preliminary notice of the reaction of nitrous acid with picramic acid and aminonitrophenol), Annalen der Chemie und Pharmacie, 106 : 123-125.

Several methods exist for the preparation of diazo compounds.{{JerryMarch}}New Syntheses of Diazo Compounds Gerhard Maas Angew. Chem. Int. Ed. 2009, 48, 8186 – 8195 {{doi|10.1002/anie.200902785}}

Alkyl-acyl nitrosamines in base dehydrate to diazo compounds:Example: Organic Syntheses, Coll. Vol. 6, p.981 (1988); Vol. 57, p.95 (1977). [http://www.orgsynth.org/orgsyn/pdfs/CV6P0981.pdf Link]

File:Diazo Synthesis.svg for an alternative.]]

Examples are the laboratory synthesis of diazomethane from diazald or MNNG.

In some cases, the nitrosamine can be produced in situ without base. Primary aliphatic amines R-CH₂-NH₂ with an α acceptor (R = COOR, CN, CHO, COR) in nitrous acid directly generate a diazo compound.

Hydrazones are oxidized (dehydrogenation) for example with silver oxide or mercury oxide for example the synthesis of {{ill|2-diazopropane|fr}} from acetone hydrazone.Organic Syntheses, Coll. Vol. 6, p.392 (1988); Vol. 50, p.27 (1970). [http://www.orgsyn.org/demo.aspx?prep=CV6P0392 Link] Other oxidizing reagents are lead tetraacetate, manganese dioxide and the Swern reagent. Tosyl hydrazones RRC=N-NHTs are reacted with base for example triethylamine in the synthesis of crotyl diazoacetateOrganic Syntheses, Coll. Vol. 5, p.258 (1973); Vol. 49, p.22 (1969). [http://www.orgsyn.org/orgsyn/prep.asp?prep=CV5P0258 Link] and in the synthesis of phenyldiazomethane from PhCHNHTs and sodium methoxide.Organic Syntheses, Coll. Vol. 7, p.438 (1990); Vol. 64, p.207 (1986).http://www.orgsyn.org/orgsyn/prep.asp?prep=CV7P0438

Reaction of a carbonyl group with the hydrazine 1,2-bis(tert-butyldimethylsilyl)hydrazine to form the hydrazone is followed by reaction with the iodane difluoroiodobenzene yields the diazo compound:{{Cite journal| last1 = Lei | first1 = X.| last2 = Porco Ja | first2 = J.| title = Total synthesis of the diazobenzofluorene antibiotic (-)-kinamycin C1| journal = Journal of the American Chemical Society| volume = 128| issue = 46| pages = 14790–14791| year = 2006| pmid = 17105273 | doi = 10.1021/ja066621v}}Elusive Natural Product Is Synthesized Stu Borman Chemical & Engineering News October 31, 2006 [http://pubs.acs.org/cen/news/84/i45/8445notw4.html Link] {{Webarchive|url=https://web.archive.org/web/20080828122002/http://pubs.acs.org/cen/news/84/i45/8445notw4.html |date=2008-08-28 }}.

:File:KinamycinCSynthesis.png

An example of an electrophilic substitution using a diazomethyl compound is that of a reaction between an acyl halide and diazomethane,Example Organic Syntheses, Coll. Vol. 3, p.119 (1955); Vol. 26, p.13 (1946).[http://www.orgsynth.org/orgsyn/pdfs/CV3P0119.pdf Link] for example the first step in the Arndt-Eistert synthesis.

File:DOXGON.png

In diazo transfer, sometimes called Regitz diazo transfer, certain carbon acids react with sulfonyl azides and a weak base like triethylamine or DBU, with corresponding sulfonamide byproduct.M. Regitz, Angew. Chem., 79, 786 (1967); Angew. Chem. Intern. Ed. Engl., 6, 733 (1967). The mechanism involves enolate attack at the terminal nitrogen, proton transfer, and sulfonamide anion expulsion.

File:Regitz.png

Historically, Regitz transferred from tosyl azide, but modern transfer uses reagents that are less explosive or more easily separated from the reaction products. These include imidazole-1-sulfonyl azide, {{ill|4-Acetamidobenzenesulfonyl azide|lt=p{{nbh}}acetanilide­sulfonyl azide|de|4-Acetamidobenzolsulfonylazid}}, and methanesulfonyl azide.{{citation|first=Gerhard |last=Maas |date=2009-10-19 |doi=10.1002/anie.200902785 |issue=44 |pages=8186–8195 |periodical=Angewandte Chemie International Edition |title=New Syntheses of Diazo Compounds |volume=48}} β-Carbonyl aldehydes undergo a deformylative variant to give primary diazo compounds stabilized by only the ketone.{{Cite book|title=Strategic Applications of Named Reactions in Organic Synthesis|author=Kurti Laszlo|date=2005|publisher=Elsevier Science|others=Czako Barbara|isbn=978-0-08-057541-4|location=Burlington|oclc=850164343}}

Simple examples synthesize tert-butyl diazoacetate,Organic Syntheses, Coll. Vol. 5, p.179 (1973); Vol. 48, p.36 (1968). [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0179 Link] diazomalonate,Organic Syntheses, Coll. Vol. 6, p.414 (1988); Vol. 59, p.66 (1979). [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0414 Link] or methyl phenyldiazoacetate (from methyl phenylacetate).{{cite journal|title=Methyl Phenyldiazoacetate|author=Huw M. L. Davies|author2=Wen-hao Hu|author3=Dong Xing|journal=EEROS|pages=1–10|doi=10.1002/047084289X.rn00444.pub2|year=2015|isbn=978-0-470-84289-8}}{{cite journal|title=3-Hydroxymethyl-3-phenylcyclopropene|first1=Ramajeyam|last1=Selvaraj|first2=Srinivasa R.|last2=Chintala|first3=Michael T.|last3=Taylor|first4=Joseph M.|last4=Fox|journal=Org. Synth.|year=2014|volume=91|page=322|doi=10.15227/orgsyn.091.0322}}

In a more complicated example, phenacyl bromide reacts with trimethylphosphite and then sodium hydride and methanesulfonyl azide to give a diazo product that converts aldehydes into alkynes. This method resembles the Ohira-Bestmann reagent but is significantly more expensive.{{citation|first1=Douglass F. |last1=Taber |first2=Sha |last2=Bai |first3=Peng-fei |last3=Guo |date=November 2008 |doi=10.1016/j.tetlet.2008.09.114 |issue=48 |pages=6904–6906 |periodical=Tetrahedron Letters |pmc=2634292 |pmid=19946355 |title=A convenient reagent for aldehyde to alkyne homologation |volume=49}}

One method is described for the synthesis of diazo compounds from azides using phosphines:A Phosphine-Mediated Conversion of Azides into Diazo Compounds Eddie L. Myers and Ronald T. Raines Angew. Chem. Int. Ed. 2009, 48, 2359 –2363 {{doi|10.1002/anie.200804689}}

:Azide to diazo conversion

Diazo compounds react as 1,3-dipoles in diazoalkane 1,3-dipolar cycloadditions.

Diazo compounds are used as precursors to carbenes, which are generated by thermolysis or photolysis, for example in the Wolff rearrangement. (In this regard, they resemble diazirenes.) As such they are used in cyclopropanation for example in the reaction of ethyl diazoacetate with styrene.Organic Syntheses, Coll. Vol. 6, p.913 (1988); Vol. 50, p.94 (1970).[http://www.orgsyn.org/orgsyn/prep.asp?prep=CV6P0913 Link] Certain diazo compounds can couple to form alkenes in a formal carbene dimerization reaction.

Diazo compounds are intermediates in the Bamford–Stevens reaction of tosylhydrazones to alkenes, again with a carbene intermediate:

:File:Bamford-Stevens reaction mechanism.svg

In the Doyle–Kirmse reaction, certain diazo compounds react with allyl sulfides to the homoallyl sulfide. Intramolecular reactions of diazocarbonyl compounds provide access to cyclopropanes. In the Buchner ring expansion, diazo compounds react with aromatic rings with ring-expansion.

The Buchner-Curtius-Schlotterbeck reaction yields ketones from aldehydes and aliphatic diazo compounds:

:File:Buchner-Curtius-Schlotterbeck Reaction.svg

The reaction type is nucleophilic addition.

Several families of naturally occurring products feature the diazo group. The kinamycins and lomaiviticin are DNA intercalating molecules, with the diazo functionality as their "warheads". In the presence of a reducing agent, loss of N₂ occurs to generate a DNA-cleaving fluorenyl radical.

One biochemical process for diazo formation is the L-aspartate-nitro-succinate (ANS) pathway. It involves a sequence of enzyme-mediated redox reactions to generate nitrite by way of a nitrosuccinic acid intermediate. This pathway appears to be active in several different Streptomyces species, and homologous genes appear widespread in actinobacteria.{{cite journal |journal= J. Antibiot. |year= 2018 |volume= 71 |issue= 11 |pages= 911–919 |doi= 10.1038/s41429-018-0088-1 |title= Novel desferrioxamine derivatives synthesized using the secondary metabolism-specific nitrous acid biosynthetic pathway in Streptomyces davawensis |first1= Ryota |last1= Hagihara |first2= Yohei |last2= Katsuyama |first3= Yoshinori |last3= Sugai |first4= Hiroyasu |last4= Onaka |first5= Yasuo |last5= Ohnishi |pmid= 30120394 }}

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