Hydrazone

Hydrazine, organohydrazines, and 1,1-diorganohydrazines react with aldehydes and ketones to give hydrazones.

:File:Hydrazone General Synthesis.svg

Phenylhydrazine reacts with reducing sugars to form hydrazones known as osazones, which was developed by German chemist Emil Fischer as a test to differentiate monosaccharides.{{cite journal|last1=Fischer|first1=Emil|year=1908|title=Schmelzpunkt des Phenylhydrazins und einiger Osazone|url=https://zenodo.org/record/1426269|journal=Berichte der Deutschen Chemischen Gesellschaft|volume=41|pages=73–77|doi=10.1002/cber.19080410120}}{{cite journal|last1=Fischer|first1=Emil|year=1894|title=Ueber einige Osazone und Hydrazone der Zuckergruppe|url=https://zenodo.org/record/1425750|journal=Berichte der Deutschen Chemischen Gesellschaft|volume=27|issue=2|pages=2486–2492|doi=10.1002/cber.189402702249}}

image:Pigment Yellow 97.svg, a popular yellow colorant, is a hydrazone.{{cite journal |doi=10.1016/j.dyepig.2005.07.001 |title=The crystal structure of CI Pigment Yellow 97, a superior performance Hansa yellow pigment |date=2006 |last1=Christie |first1=R. |last2=Hill |first2=J. |last3=Rosair |first3=G. |journal=Dyes and Pigments |volume=71 |issue=3 |pages=194–198 }}|160px]]

Hydrazones are the basis for various analyses of ketones and aldehydes. For example, dinitrophenylhydrazine coated onto a silica sorbent is the basis of an adsorption cartridge. The hydrazones are then eluted and analyzed by high-performance liquid chromatography (HPLC) using a UV detector.

The compound carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (abbreviated as FCCP) is used to uncouple ATP synthesis and reduction of oxygen in oxidative phosphorylation in molecular biology.

Hydrazones are the basis of bioconjugation strategies.{{cite journal |doi=10.1021/acs.chemrev.7b00090|title=Oximes and Hydrazones in Bioconjugation: Mechanism and Catalysis|year=2017|last1=Kölmel|first1=Dominik K.|last2=Kool|first2=Eric T.|journal=Chemical Reviews|volume=117|issue=15|pages=10358–10376|pmid=28640998|pmc=5580355}}{{cite journal |doi=10.1021/bc200065z|title=The Controlled Display of Biomolecules on Nanoparticles: A Challenge Suited to Bioorthogonal Chemistry|year=2011|last1=Algar|first1=W. Russ|last2=Prasuhn|first2=Duane E.|last3=Stewart|first3=Michael H.|last4=Jennings|first4=Travis L.|last5=Blanco-Canosa|first5=Juan B.|last6=Dawson|first6=Philip E.|last7=Medintz|first7=Igor L.|journal=Bioconjugate Chemistry|volume=22|issue=5|pages=825–858|pmid=21585205}} Hydrazone-based coupling methods are used in medical biotechnology to couple drugs to targeted antibodies (see ADC), e.g. antibodies against a certain type of cancer cell. The hydrazone-based bond is stable at neutral pH (in the blood), but is rapidly destroyed in the acidic environment of lysosomes of the cell. The drug is thereby released in the cell, where it exerts its function.{{Cite journal | last1 = Wu | first1 = Anna M. | last2 = Senter | first2 = Peter D. | title = Arming antibodies: prospects and challenges for immunoconjugates | journal = Nature Biotechnology | volume = 23 | issue = 9 | pages = 1137–46 | date = 7 September 2005 | doi = 10.1038/nbt1141 | pmid=16151407| s2cid = 27226728 }}

Hydrazones are susceptible to hydrolysis:

:{{chem2|R2C\dN\sNR'2 + H2O → R2C\dO + H2N\sNR'2}}

Alkyl hydrazones are 10²- to 10³-fold more sensitive to hydrolysis than analogous oximes.{{Cite journal |last1=Kalia |first1=J. |last2=Raines |first2=R. T. |title=Hydrolytic stability of hydrazones and oximes |journal=Angew. Chem. Int. Ed. |year=2008 |volume=47 |pmid=18712739 |issue=39 |pages=7523–6 |pmc=2743602 |doi=10.1002/anie.200802651}}

When derived from hydrazine itself, hydrazones condense with a second equivalent of a carbonyl to give azines:{{OrgSynth | first1 = A. C. | last1 = Day | first2 = M. C. | last2 = Whiting | title = Acetone Hydrazone | volume = 50 | pages = 3 | year = 1970 | doi= 10.15227/orgsyn.050.0003}}

:{{chem2|R2C\dN\sNH2 + R2C\dO → R2C\dN\sN\dCR2 + H2O}}

Hydrazones are intermediates in the Wolff–Kishner reduction.

Hydrazones are reactants in hydrazone iodination, the Shapiro reaction, and the Bamford–Stevens reaction to vinyl compounds. Hydrazones can also be synthesized by the Japp–Klingemann reaction via β-keto acids or β-keto-esters and aryl diazonium salts. Hydrazones are converted to azines when used in the preparation of 3,5-disubstituted 1H-pyrazoles,{{cite journal|title = Metal-free and FeCl₃-catalyzed synthesis of azines and 3,5-diphenyl-1H-pyrazole from hydrazones and/or ketones monitored by high resolution ESI⁺-MS|year = 2018|journal = Indian Journal of Chemistry, Section B|volume = 57B|issue = 3|pages = 362–373|url = http://nopr.niscair.res.in/handle/123456789/43824|first1 = Jamal|last1 = Lasri|first2 = Ali I.|last2 = Ismail}} a reaction also well known using hydrazine hydrate.{{cite journal|title = New one step synthesis of 3,5-disubstituted pyrazoles under microwave irradiation and classical heating|year = 2008|journal = Journal of Heterocyclic Chemistry|volume = 45|issue = 2|pages = 503–505|doi = 10.1002/jhet.5570450231|first1 = Moha|last1 = Outirite|first2 = Mounim|last2 = Lebrini|first3 = Michel|last3 = Lagrenée|first4 = Fouad|last4 = Bentiss}}{{cite journal|title = One-pot synthesis of 3,5-diphenyl-1H-pyrazoles from chalcones and hydrazine under mechanochemical ball milling|year = 2014|journal = Heterocycles|volume = 89|issue = 1|pages = 103–112|doi = 10.3987/COM-13-12867|first1 = Ze|last1 = Zhang|first2 = Ya-Jun|last2 = Tan|first3 = Chun-Shan|last3 = Wang|first4 = Hao-Hao|last4 = Wu|doi-access = free}} With a transition metal catalyst, hydrazones can serve as organometallic reagent surrogates to react with various electrophiles.{{cite journal|title = Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds|year = 2017|journal = Nature Chemistry|volume = 9|pages = 374–378|doi = 10.1038/nchem.2677|first1 = H|last1 = Wang|first2 = X.-J.|last2 = Dai|first3 = C.-J.|last3 = Li|issue = 4| pmid=28338683 |s2cid = 11653420}}

:700px

{{Main|Enders SAMP/RAMP hydrazone alkylation reaction}}

In N,N-dialkylhydrazones{{Cite journal| doi = 10.1021/cr900067y| pmid = 20000672| year = 2010| last1 = Lazny | first1 = R.| last2 = Nodzewska | first2 = A.| title = N,N-dialkylhydrazones in organic synthesis. From simple N,N-dimethylhydrazones to supported chiral auxiliaries| volume = 110| issue = 3| pages = 1386–1434| journal = Chemical Reviews}} the C=N bond can be hydrolysed, oxidised and reduced, the N–N bond can be reduced to the free amine. The carbon atom of the C=N bond can react with organometallic nucleophiles. The alpha-hydrogen atom is more acidic by 10 orders of magnitude compared to the ketone and therefore more nucleophilic. Deprotonation with for instance lithium diisopropylamide (LDA) gives an azaenolate which can be alkylated by alkyl halides.{{Cite journal| doi = 10.1016/S0957-4166(97)00208-5| title = Asymmetric synthesis of amines by nucleophilic 1,2-addition of organometallic reagents to the CN-double bond| year = 1997| last1 = Enders| first1 = Dieter| last2 = Reinhold| first2 = Ulrich| journal = Tetrahedron: Asymmetry| volume = 8| issue = 12| pages = 1895–1946}} The hydrazines SAMP and RAMP function as chiral auxiliary.{{cite journal | first1 = Dieter | last1 = Enders | first2 = Peter | last2 = Fey | first3 = Helmut | last3 = Kipphardt | title = (S)-(−)-1-Amino-2-methoxymethylpyrrolidine (SAMP) and (R)-(+)-1-amino-2-methoxymethylpyrrolidine (RAMP), Versatile Chiral Auxiliaries | journal = Organic Syntheses | volume = 65 | pages = 173 | year = 1987 | doi = 10.15227/orgsyn.065.0173| s2cid = 260330996 }}{{cite journal | first1 = Dieter | last1 = Enders | first2 = Helmut | last2 = Kipphardt | first3 = Peter | last3 = Fey | title = Asymmetric Syntheses Using the SAMP-/RAMP-Hydrazone Method: (S)-(+)-4-methyl-3-heptanone | journal = Organic Syntheses | volume = 65 | pages = 183 | year = 1987 | doi=10.15227/orgsyn.065.0183}}

:File:SAMP RAMP Struktur.svg

Several methods are known to recover carbonyl compounds from N,N-dialkylhydrazones.{{Cite journal |title=Recovery of Carbonyl Compounds from N,N-Dialkylhydrazones |url=https://pubs.acs.org/doi/10.1021/ar990062y |journal=Accounts of Chemical Research|date=2000 |doi=10.1021/ar990062y |last1=Enders |first1=Dieter |last2=Wortmann |first2=Lars |last3=Peters |first3=René |volume=33 |issue=3 |pages=157–169 |pmid=10727205 |url-access=subscription }} Procedures include oxidative, hydrolytic or reductive cleavage conditions and can be compatible with a wide range of functional groups.

File:Benzophenone hydrazone-structure.png|Benzophenone hydrazone, an illustrative hydrazone

File:Carbonyl cyanide m-chlorophenyl hydrazone.svg|Carbonyl cyanide m-chlorophenyl hydrazone

File:Gyromitrin.svg| Gyromitrin (acetaldehyde methylformylhydrazone), a toxin

File:Dihydralazine structure.svg| Dihydralazine, an antihypertensive drug

File:NERYOZ.png|X-ray structure of DNP-derived hydrazone of benzophenone. Selected parameters: C=N, 128 pm; N-N, 138 pm, N-N-C(Ar), 119 pm{{cite journal |doi=10.1107/S1600536806048112|title=Benzophenone 2,4-dinitrophenylhydrazone|year=2006|last1=Tameem|first1=Abdassalam Abdelhafiz|last2=Salhin|first2=Abdussalam|last3=Saad|first3=Bahruddin|last4=Rahman|first4=Ismail Ab.|last5=Saleh|first5=Muhammad Idiris|last6=Ng|first6=Shea-Lin|last7=Fun|first7=Hoong-Kun|journal=Acta Crystallographica Section E|volume=62|issue=12|pages=o5686–o5688}}

• Azo compound
• Imine
• Nitrosamine
• Hydrogenation of carbon–nitrogen double bonds

{{Reflist}}

{{Functional group}}

{{Hydrazines}}

{{Authority control}}

Category:Functional groups