Osazones formation mechanism

Fig. 3.12. Osazone formation mechanism by the addition of three phenylhydrazine molecules to one aldose molecule...

These recent investigations may lead to further clarification of the mechanism of osazone formation, one of the classical sugar reactions. 

Scheme B requires exchange of the H-l with the medium, whereas Scheme A does not. Despite a report5 that stated that there was no loss of tritium from D-glucose-i-f on osazone formation, it seems that about 15% of the hydrogen on C-l does undergo exchange. Such an exchange is consistent with the operation of mechanism B, with a large isotope-effect, but does not preclude the simultaneous operation of mechanism A.

Weygand has suggested two possible mechanisms for osazone formation which depend on the occurrence of an Amadori rearrangement after initial condensation of the hydrazine with the carbonyl group.Both routes were presented and reviewed by Percival in Volume 3 of this Series. Since that time, Weygand s theory has remained valid. Criticism by Ruggli and Zeller was satisfactorily answered by Weygand and Reckhaus, who showed that... 

The mechanism of osazone formation has been studied by the isotopic-tracer technique, by using an N -labeled arylhydrazone, treating it with an unlabeled arylhydrazone, and making an isotopic assay of the reaction products. The results were characteristic of Weygand s mechanism involving the oxidation of the hydrazone to a l-imino-lV -2-keto derivative (40) and subsequent osazone formation with the elimination of ammonia-iV . 

Figure 6.17 Alternative mechanisms of osazone formation. In pathway A all the labelled nitrogen appears as ammonia, and in pathway B less (in the case of symmetrical systems such as benzoin, half).

According to Micheel, osazone formation starts from an aldose and requires an Amadori rearrangement, so that his scheme may not account for the reaction in the ketose series. It may be concluded that the Fischer mechanism is not valid, and that further studies are needed in order to solve the problem of interaction between ketoses and substituted phenyl-hydrazines. 

Two variations of the Weygand mechanism have been suggested which include both an Amadori rearrangement and an oxidation reaction. The first was that of Barry and Mitchell, who based their mechanism on the observation that 1,2-disubstituted hydrazines of the type (31) are readily oxidized in air to the corresponding hydrazone (32). They suggested that, as osazone formation requires the presence of air, a similar oxidation... 

A study of the scope of this reaction has been performed which shows that excess phenylhydrazine will convert the disubstituted quinoxalines 19 into the pyrazolo[3,4-h]quinoxaline 20. Analogously hydroxylamine gave the isoxazolo compound 21 from these starting materials. The compounds 19 (R = Me or Ph) did not undergo cyclization with phenylhydrazine. A reaction mechanism has been suggested (see Scheme 1) which is analogous to osazone formation in sugar chemistry. 

In the controversy on the mechanism of osazone formation, it was found that glucose-f-t is converted into the phenylosazone and the phenyl-osotriazole without loss of tritium." This finding was taken as evidence against formation, by the Amadori rearrangement, of an intermediate having two hydrogen atoms on C-1 as in Weygand s scheme" B. 

The mechanism for osazone formation probably depends on a series of reactions in which C=N behaves very much like C=0 in giving a nitrogen version of an enol. 

Ribofuranosyl derivatives of substituted benzimidazoles have been found to have virus inhibitory activity (44)-From glucosone, compounds with quinoxaline structures may be produced (4S), In the presence of hydrazine and o-phenylenediamine, 1-deoxy-1-p-toluino-D-fructose or -D-tagatose is converted to a quinoxaline compound in the pH range 6 to 8 by a mechanism similar to osazone formation 46),... 

A mechanism of osazone formation utilizing the same intermediate (III) as the Weygand-Reckhaus mechanism (I-VII) has been proposed by Bloink and Pausacker The key step may be the formation of a cyclic transition state (III ) between the intermediate (III) and a molecule of phenyl-hydrazine hydrochloride which is reductively cleaved to yield the osazone (VIP) directly as well as ammonia and aniline simultaneously. 

Many years later, several groups conducted investigations into the mechanism of the osazone formation steps and concluded that an Amadori rearrangement is involved in this reaction cascade [18] (Scheme 5,14 to 16). Aldoses 14... 

The rather peculiar, catalytic role of acetic acid was also mentioned it favors formation of the osazone without the necessity for any excess of the substituted hydrazine, in contrast with the formation of hydrazones when alcohol is the solvent. These results agree with a mechanism proposed by Butler and Cretcher, and were confirmed by analysis of the reaction products. n-Glucose (2,3-dichlorophenyl)hydrazone (28) yielded the osa-... 

The mixed osazones prepared by Henseke and Binte during studies on the osones and related compounds brought forth new facts regarding the mechanism of formation. They postulated a linkage of glycosyl to nitrogen, whereas the bond between a disubstituted hydrazine residue and C-2 is veiy labile and is subject to hydrazone wandering. 

Ingles heated a solution of n-glucose, sodium sulfite, and bisulfite, removed the cations, and steam-distilled the residue. The product, free of carbonyl-bisulfite addition compounds, was chromatographed on an ion-exchange resin, giving a sulfonic acid. This acid yields a crystalline brucine salt and phenyl- and (2,4-dinitrophenyl)-osazones. The osazones consume 1 mole of periodate per mole, liberating 1 mole of formaldehyde but no formic acid. The (2,4-dinitrophenyl)osazone also forms a diacetate. The acid is oxidized by sodium hypoiodite, taking up 1 mole of oxidant per mole. From these reactions and the possible reaction mechanisms for its formation, structure (41), a 3,4-dideoxy-4-sulfo-n-hexosulose, was proposed for the sulfonic acid. ... 

Furthermore, aniline was found to increasei the rate of formation of the osazone by ten percent, a fact which cannot be explained in the light of Fischer s mechanism, as it would tend to shift the equilibrium away from the osazone. 

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