Chemistry:Hydrazone

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Short description: Organic compounds - Hydrazones
Structure of the hydrazone functional group

Hydrazones are a class of organic compounds with the structure R1
R2
C=N–NH
2.[1] They are related to ketones and aldehydes by the replacement of the oxygen =O with the =N–NH
2 functional group. They are formed usually by the action of hydrazine on ketones or aldehydes.[2][3]

Synthesis

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

Hydrazone synthesis

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.[4][5]

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.[6][7] 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.[8]

Reactions

Hydrazones are susceptible to hydrolysis:

R
2C=N–NR'
2 + H
2O → R
2C=O + H
2N–NR'
2

Alkyl hydrazones are 102- to 103-fold more sensitive to hydrolysis than analogous oximes.[9]

When derived from hydrazine itself, hydrazones condense with a second equivalent of a carbonyl to give azines:[10]

R
2C=N–NH
2 + R
2C=O → R
2C=N–N=CR
2 + H
2O

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,[11] a reaction also well known using hydrazine hydrate.[12][13] With a transition metal catalyst, hydrazones can serve as organometallic reagent surrogates to react with various electrophiles.[14]

Lasri condensation reaction.svg

N,N-dialkylhydrazones

In N,N-dialkylhydrazones[15] 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.[16] The hydrazines SAMP and RAMP function as chiral auxiliary.[17][18]

SAMP RAMP chiral auxiliaries

Recovery of carbonyl compounds from N,N-dialkylhydrazones

Several methods are known to recover carbonyl compounds from N,N-dialkylhydrazones.[19] Procedures include oxidative, hydrolytic or reductive cleavage conditions and can be compatible with a wide range of functional groups.

Gallery

See also

References

  1. ↑ March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7 
  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. http://www.orgsyn.org/demo.aspx?prep=cv6p0242. ; Collective Volume, 6, pp. 242 
  3. ↑ Day, A. C.; Whiting, M. C. (1970). "Acetone hydrazone". Organic Syntheses 50: 3. http://www.orgsyn.org/demo.aspx?prep=cv6p0010. ; Collective Volume, 6, pp. 10 
  4. ↑ Fischer, Emil (1908). "Schmelzpunkt des Phenylhydrazins und einiger Osazone". Berichte der Deutschen Chemischen Gesellschaft 41: 73–77. doi:10.1002/cber.19080410120. https://zenodo.org/record/1426269. 
  5. ↑ Fischer, Emil (1894). "Ueber einige Osazone und Hydrazone der Zuckergruppe". Berichte der Deutschen Chemischen Gesellschaft 27 (2): 2486–2492. doi:10.1002/cber.189402702249. https://zenodo.org/record/1425750. 
  6. ↑ 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. PMID 28640998. 
  7. ↑ 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. 
  8. ↑ 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. 
  9. ↑ 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. PMID 18712739. 
  10. ↑ Day, A. C.; Whiting, M. C. (1970). "Acetone Hydrazone". Organic Syntheses 50: 3. doi:10.15227/orgsyn.050.0003. 
  11. ↑ 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. http://nopr.niscair.res.in/handle/123456789/43824. 
  12. ↑ 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. 
  13. ↑ 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. 
  14. ↑ 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. 
  15. ↑ 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. 
  16. ↑ 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. 
  17. ↑ Enders, Dieter; Fey, Peter; Kipphardt, Helmut (1987). "(S)-(−)-1-Amino-2-methoxymethylpyrrolidine (SAMP) and (R)-(+)-1-amino-2-methoxymethylpyrrolidine (RAMP), Versatile Chiral Auxiliaries". Organic Syntheses 65: 173. doi:10.15227/orgsyn.065.0173. 
  18. ↑ 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. 
  19. ↑ "Recovery of Carbonyl Compounds from N,N-Dialkylhydrazones". Accounts of Chemical Research. https://pubs.acs.org/doi/10.1021/ar990062y. 
  20. ↑ 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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