Semicarbazide1

[57-56-7]  · CH5N3O  · Semicarbazide  · (MW 75.09) (HCl salt)

[563-41-7]  · CH6ClN3O  · Semicarbazide Hydrochloride  · (MW 111.55)

(potent nucleophile; forms many crystalline carbonyl derivatives1)

Physical Data: HCl salt: mp 175-177 °C (dec).

Solubility: HCl salt: relatively sol water.

Form Supplied in: the HCl salt is widely available from commercial suppliers as a crystalline material; it can be further purified by recrystallization from 75% aq. ethanol and dried under vacuum over calcium sulfate.2

Handling, Storage, and Precautions: reactive nucleophile with significant ability to bind to various enzymes; exercise reasonable caution.

Derivatization.

The most straightforward use of semicarbazide is in its reaction with the carbonyl group of aldehydes and ketones (eq 1) to afford derivatives known as semicarbazones.3 These semicarbazones are commonly crystalline with characteristic melting points. An excellent procedure for isolation of aldehydes and/or ketones from other functionalized materials in a mixture is to heat that mixture with semicarbazide on a silica gel support, filter off the solid, and regenerate the carbonyl compound by heating the support with oxalic acid in a two-phase aqueous/organic system.4

Role as a Nucleophile.

Semicarbazide often serves as a typical nucleophilic reagent in studies involving carbonyl chemistry. The mechanism of semicarbazone formation has been repeatedly studied.5 Many fundamental physical organic studies have been published on the interconversion of a trigonal carbonyl carbon into a tetrahedral carbon intermediate. Investigations focusing on generation of these tetrahedral intermediates, especially the formation of carbinolamines via addition of nitrogen-containing nucleophiles (eq 2), have often employed semicarbazide as a reactant.6 These include specialized experimental studies such as examination of secondary isotope effects7 and proton NMR.8 Because of the presence of the two adjacent nitrogen atoms in semicarbazide, this molecule has figured prominently in several studies of the so-called a effect.9 Semicarbazide has often been employed in comparisons of relative nucleophilicity.10 Especially significant are the many investigations of aminolysis.11 Application of this research to enzymes has been extensive, as is illustrated by work on arylamine N-acetyltransferase,12 monoamine oxidase,13 urease,14 chymotrypsin,15 N-methylglutamate synthetase,16 and pyruvamide-dependent histidine decarboxylase.17 A comparison of semicarbazide with other nucleophiles in nucleophilic aromatic substitution (eq 3) has been published.18 Diaryl and heteroaryl disulfides are cleaved to the corresponding thiols by semicarbazide.19

Generation of Heterocycles.

Conversion of cyclic ketones to semicarbazones followed by Selenium(IV) Oxide oxidation produces 1,2,3-selenadiazoles. Pyrolysis of the selenadiazole affords the corresponding cycloalkyne (eq 4).20 Conversion of a pyranulose glycoside to the semicarbazone, reaction with HCl/dioxane, and heating in acetic acid leads to the novel triazine (1) (eq 5).21 The antimicrobial activity of the nitrofurans has inspired a tremendous effort directed at the preparation of analogs. Many of these have involved elaboration of various appended side chains by reaction of the carbonyl functionality with semicarbazide.22 Reaction of semicarbazide with enones23 (eq 6) and ynones24 with subsequent dehydration provides an efficient route to pyrazole derivatives. Certain pyrimidines can be made to undergo ring-contraction to pyrazoles by heating with semicarbazide in an acidic medium (eq 7).25 Reaction of a-hydroxymethylene ketones with semicarbazide has been shown26 to generate pyrazoline derivatives (eq 8). a-Diketones afford as-triazines upon reaction with semicarbazide followed by dehydration and hydrogenolysis (eq 9).27 Heating of an acylanthranilic acid in the presence of semicarbazide provides the corresponding 2,3-disubstituted 4-oxo-3,4-dihydroquinazoline.28 Reaction of dithioesters with semicarbazide with subsequent dehydration and aromatization has been employed for the preparation of thiadiazoles.29 In an investigation of heterocyclic quinones, combination of semicarbazide with 6-chloroquinoline-5,8-dione hydrochloride provided a reasonable yield of oxadiazino[6,5-g]quinoline-5,10-dione (eq 10).30

Applications to Biological Chemistry.

In studies concerned with the effects of atmospheric pollutants on erythrocyte membranes, semicarbazide has been utilized as an ozone scavenger.31 The effect of semicarbazide on the course of various photochemical processes that occur in chloroplasts has been investigated.32 In reconstitution experiments, semicarbazide has a significant effect on collagen fiber formation and properties.33

Related Reagents.

N,N-Dimethylhydrazine; Hydrazine; Hydroxylamine; Phenylhydrazine.


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John L. Belletire & R. Jeffery Rauh

The University of Cincinnati, OH, USA



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