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−NH2functional 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.
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:
R2C=N−NR'2 + H2O → R2C=O + H2N−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]
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]
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.
^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.
PMID21585205.
^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.
PMID16151407.
S2CID27226728.
^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.
PMID20000672.
^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.