Hydrazone

Hydrazones are a class of organic compounds with the structure R1R2C=N−NH2.[1] They are related to ketones and aldehydes by the replacement of the oxygen =O with the =N−NH2 functional group. They are formed usually by the action of hydrazine on ketones or aldehydes.[2][3]

Synthesis

Hydrazine, its hydrate,[4][5] and various organohydrazines react with aldehydes and ketones to give hydrazones:

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.[6][7] Hydrazones having 1,3-diketomoiety are also known in literature.[8]

More generally, diazonium ions react with carbon acids in the Japp-Klingemann reaction to give hydrazones via tautomeric rearrangement of a diazo intermediate.[9]

Uses

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.[11][12] 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.[13]

Reactions

Hydrazones carry two heteroatoms: a double-bonded "imine nitrogen", and a single-bonded "amine nitrogen". Reactivity arises predominantly from the amine nitrogen, which is basic and nucleophilic. When the amine nitrogen is unsubstituted, the hydrazone can condense with a second equivalent of a carbonyl to give azines, e.g.:[14][15]

The nitrogen atom also stabilizes the development of negative charge at the double-bonded carbon atom, umpoling the carbonyl. Aldehydic hydrazones undergo electrophilic substitution there; for example benzylium cations react to give the corresponding ketonic hydrazone.[16] In base, they simply deprotonate: similar to oxime dehydration, they eliminate the amine nitrogen to give a nitrile.[17]

The behavior of ketonic hydrazones in base is more complicated, as they have no aldehydic proton to lose. If the amine nitrogen is unsubstituted, then the molecule can undergo the Wolff–Kishner reduction: first, it deprotonates at the amine nitrogen and then reprotonates at the carbon. The resulting hydrazo compound is unstable and decomposes to an alkane,[18] but can be intercepted to perform a Grignard-like addition.[19]

If the amine nitrogen is instead fully substituted, then the next proton to leave is α to the double-bonded carbon, restoring conventional carbonyl polarity.[20] As such, the amine nitrogen is a convenient location for a chiral auxiliary.[21] This idea is the Enders SAMP/RAMP alkylation and its descendants.[22]

Hydrolysis, which would require another umpolung, is generally a difficult reaction for hydrazones. Nevertheless, alkyl hydrazones are 102- to 103-fold more susceptible to hydrolysis than analogous oximes.[23] The reaction can be performed reliably with BiCl3 acid catalysis.[17] Alternatively, acylation of the amine nitrogen, which reduces its basicity, makes hydrolysis possible with tosylic acid.[24]

Other reactions exploit hydrazones' similarity to the diazo and alkene functionalities. In the Shapiro reaction and descendants (hydrazone iodination and the Bamford–Stevens reaction), α elimination converts a sulfonamidrazone to the diazo, which then decomposes to vinyl compounds.[25] In variants on the Lemieux–Johnson oxidation, strong oxidants peroxidize the imine nitrogen's double-bond to carbon, recovering the carbonyl and a nitrosamine.[17]

Some reductants cleave the nitrogen-nitrogen bond.[17]

See also

References

  1. ^ March, Jerry (1985). Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.). New York: Wiley. ISBN 9780471854722. OCLC 642506595.
  2. ^ Stork, G.; Benaim, J. (1977). "Monoalkylation of α,β-Unsaturated Ketones via Metalloenamines: 1-butyl-10-methyl-Δ1(9)-2-octalone". Organic Syntheses. 57: 69; Collected Volumes, vol. 6, p. 242.
  3. ^ Day, A. C.; Whiting, M. C. (1970). "Acetone hydrazone". Organic Syntheses. 50: 3; Collected Volumes, vol. 6, p. 10.
  4. ^ Outirite, Moha; Lebrini, Mounim; Lagrenée, Michel; Bentiss, Fouad (2008). "New one step synthesis of 3,5-disubstituted pyrazoles under microwave irradiation and classical heating". Journal of Heterocyclic Chemistry. 45 (2): 503–505. doi:10.1002/jhet.5570450231.
  5. ^ Zhang, Ze; Tan, Ya-Jun; Wang, Chun-Shan; Wu, Hao-Hao (2014). "One-pot synthesis of 3,5-diphenyl-1H-pyrazoles from chalcones and hydrazine under mechanochemical ball milling". Heterocycles. 89 (1): 103–112. doi:10.3987/COM-13-12867.
  6. ^ Fischer, Emil (1908). "Schmelzpunkt des Phenylhydrazins und einiger Osazone". Berichte der Deutschen Chemischen Gesellschaft. 41: 73–77. doi:10.1002/cber.19080410120.
  7. ^ Fischer, Emil (1894). "Ueber einige Osazone und Hydrazone der Zuckergruppe". Berichte der Deutschen Chemischen Gesellschaft. 27 (2): 2486–2492. doi:10.1002/cber.189402702249.
  8. ^ Singh, Raman; Halve, Anand K. (2025-06-28). "Synthesis of New Hydrazones Containing 1,3-Diketo Moiety". RSYN Chemical Sciences. 2 (1): 1–6. doi:10.70130/RCS.2025.0201001.
  9. ^ Parmerter, Stanley M. (1959). "The coupling of diazonium salts with aliphatic carbon atoms". Organic Reactions. Vol. 10. doi:10.1002/0471264180.or010.01.
  10. ^ Christie, R.; Hill, J.; Rosair, G. (2006). "The crystal structure of CI Pigment Yellow 97, a superior performance Hansa yellow pigment". Dyes and Pigments. 71 (3): 194–198. doi:10.1016/j.dyepig.2005.07.001.
  11. ^ Kölmel, Dominik K.; Kool, Eric T. (2017). "Oximes and Hydrazones in Bioconjugation: Mechanism and Catalysis". Chemical Reviews. 117 (15): 10358–10376. doi:10.1021/acs.chemrev.7b00090. PMC 5580355. PMID 28640998.
  12. ^ Algar, W. Russ; Prasuhn, Duane E.; Stewart, Michael H.; Jennings, Travis L.; Blanco-Canosa, Juan B.; Dawson, Philip E.; Medintz, Igor L. (2011). "The Controlled Display of Biomolecules on Nanoparticles: A Challenge Suited to Bioorthogonal Chemistry". Bioconjugate Chemistry. 22 (5): 825–858. doi:10.1021/bc200065z. PMID 21585205.
  13. ^ Wu, Anna M.; Senter, Peter D. (7 September 2005). "Arming antibodies: prospects and challenges for immunoconjugates". Nature Biotechnology. 23 (9): 1137–46. doi:10.1038/nbt1141. PMID 16151407. S2CID 27226728.
  14. ^ Day, A. C.; Whiting, M. C. (1970). "Acetone Hydrazone". Organic Syntheses. 50: 3. doi:10.15227/orgsyn.050.0003.
  15. ^ Lasri, Jamal; Ismail, Ali I. (2018). "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". Indian Journal of Chemistry, Section B. 57B (3): 362–373.
  16. ^ Maji, Biplab; Troshin, Konstantin; Mayr, Herbert (2013-11-04). "Ambident Reactivities of Formaldehyde N , N ‐Dialkylhydrazones". Angewandte Chemie International Edition. 52 (45): 11900–11904. doi:10.1002/anie.201305092. ISSN 1433-7851.
  17. ^ a b c d Enders, Dieter; Wortmann, Lars; Peters, René (2000). "Recovery of Carbonyl Compounds from N,N-Dialkylhydrazones". Accounts of Chemical Research. 33 (3): 157–169. doi:10.1021/ar990062y. PMID 10727205.
  18. ^ Szmant, H. H. (1968). "The Mechanism of the Wolff-Kishner Reduction, Elimination, and Isomerization Reactions". Angewandte Chemie International Edition in English. 7 (2): 120–128. doi:10.1002/anie.196801201.
  19. ^ Wang, H; Dai, X.-J.; Li, C.-J. (2017). "Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds". Nature Chemistry. 9 (4): 374–378. doi:10.1038/nchem.2677. PMID 28338683. S2CID 11653420.
  20. ^ Enders, Dieter; Reinhold, Ulrich (1997). "Asymmetric synthesis of amines by nucleophilic 1,2-addition of organometallic reagents to the CN-double bond". Tetrahedron: Asymmetry. 8 (12): 1895–1946. doi:10.1016/S0957-4166(97)00208-5.
  21. ^ Lazny, R.; Nodzewska, A. (2010). "N,N-dialkylhydrazones in organic synthesis. From simple N,N-dimethylhydrazones to supported chiral auxiliaries". Chemical Reviews. 110 (3): 1386–1434. doi:10.1021/cr900067y. PMID 20000672.
  22. ^ Enders, Dieter; Kipphardt, Helmut; Fey, Peter (1987). "Asymmetric Syntheses Using the SAMP-/RAMP-Hydrazone Method: (S)-(+)-4-methyl-3-heptanone". Organic Syntheses. 65: 183. doi:10.15227/orgsyn.065.0183.
  23. ^ Kalia, J.; Raines, R. T. (2008). "Hydrolytic stability of hydrazones and oximes". Angew. Chem. Int. Ed. 47 (39): 7523–6. doi:10.1002/anie.200802651. PMC 2743602. PMID 18712739.
  24. ^ Wengryniuk, S. E.; Lim, D.; Coltart, D. M. (2011). "Regioselective Asymmetric α,α-Bisalkylation of Ketones via Complex-Induced Syn-Deprotonation of Chiral N-Amino Cyclic Carbamate Hydrazones". Journal of the American Chemical Society. 133 (22): 8714–8720. doi:10.1021/ja202267k. PMID 21510644.
  25. ^ 吕, 萍 (2022). 中级有机化学--反应与机理 [Intermediate Organic Chemistry--Reactions and Mechanisms] (in Chinese) (2nd ed.). 高等教育出版社. pp. 279–280. ISBN 978-7-04-058063-1.
  26. ^ Tameem, Abdassalam Abdelhafiz; Salhin, Abdussalam; Saad, Bahruddin; Rahman, Ismail Ab.; Saleh, Muhammad Idiris; Ng, Shea-Lin; Fun, Hoong-Kun (2006). "Benzophenone 2,4-dinitrophenylhydrazone". Acta Crystallographica Section E. 62 (12): o5686–o5688. doi:10.1107/S1600536806048112.
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