Hydrazone

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Structure of the hydrazone functional group

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

Hydrazone synthesis

Uses[edit]

The formation of aromatic hydrazone derivatives is used to measure the concentration of low molecular weight aldehydes and ketones, e.g. in gas streams. For example, dinitrophenylhydrazine coated onto a silica sorbent is the basis of an adsorption cartridge. The hydrazones are then eluted and analyzed by 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. Phenylhydrazine reacts with glucose to form an osazone.

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.[4]

In aqueous solution, aliphatic hydrazones are 102- to 103-fold more sensitive to hydrolysis than analogous oximes.[5]

Reactions[edit]

Hydrazones are reactants in hydrazone iodination, the Shapiro reaction and the Bamford-Stevens reaction to vinyl compounds. A hydrazone is an intermediate in the Wolff–Kishner reduction. Hydrazones can also be synthesized by the Japp–Klingemann reaction via β-keto-acids or β-keto-esters and aryl diazonium salts.

N,N′-dialkylhydrazones[edit]

In N,N′-dialkylhydrazones[6] the C=N bond can be hydrolysed, oxidised and reduced, the N-N bond can be reduced to the free amine. The carbon atom if 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 LDA gives an azaenolate which can be alkylated by alkyl halides, a reaction pioneered by E.J. Corey and Dieter Enders in 1978.[7][8] In asymmetric synthesis SAMP and RAMP are two chiral hydrazines that act as chiral auxiliary with a chiral hydrazone intermediate.[9][10][11]

SAMP RAMP chiral auxiliaries

Gallery[edit]

References[edit]

  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, Org. Synth. 57: 69 ; Coll. Vol. 6: 242 
  3. ^ Day, A. C.; Whiting, M. C. (1970), Acetone hydrazone, Org. Synth. 50: 3 ; Coll. Vol. 6: 10 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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.  edit
  7. ^ Corey, E.; Enders, D. (1976). "Applications of N,N-dimethylhydrazones to synthesis. Use in efficient, positionally and stereochemically selective C_C bond formation; oxidative hydrolysis to carbonyl compounds". Tetrahedron Letters 17 (1): 3–3. doi:10.1016/S0040-4039(00)71307-4.  edit
  8. ^ Corey, E. J.; Enders, D. (1978). "Herstellung und synthetische Verwendung von metallierten Dimethylhydrazonen Regio- und stereoselektive Alkylierung von Carbonylverbindungen". Chemische Berichte 111 (4): 1337. doi:10.1002/cber.19781110413.  edit
  9. ^ Enders, D.; Eichenauer, H. (1977). "Enantioselective alkylation of aldehydes via metalated chiral hydrazones". Tetrahedron Letters 18 (23): 191–194. doi:10.1016/S0040-4039(01)92585-7.  edit
  10. ^ Enders, Dieter; Fey, Peter; Kipphardt, Helmut (1987), (S)-(−)-1-Amino-2-methoxymethylpyrrolidine (SAMP) and (R)-(+)-1-amino-2-methoxymethylpyrrolidine (RAMP), versatile chiral auxiliaries, Org. Synth. 65: 173 ; Coll. Vol. 8: 26 
  11. ^ Enders, Dieter; Kipphardt, Helmut; Fey, Peter (1987), Asymmetric syntheses using the SAMP-/RAMP-hydrazone method: (S)-(+)-4-methyl-3-heptanone, Org. Synth. 65: 183 ; Coll. Vol. 8: 403