Saccharin, formation

Side-chain oxidations of alkyl aromatic compounds to aromatic carboxylic acids by electrogenerated and regenerated chromic acid have been studied extensively in the case of saccharin formation from o-toluene sulfonamide This... 

Successive elimination of an alkoxy group adjacent to an active hydrogen atom and intramolecular Cannizzaro reactions in alkaline solution, such as are found in saccharinate formation, are demonstrated by the conversion of 2-hydroxy-3-methoxy-3-phenylpropiophenone (X) to a salt of 2,3-diphenyllactic acid (XI). 

In the formation of C6 acids (namely, organic acids containing 6 or fewer carbon atoms), at OH concentrations greater than 10 mM, route 5 occurs preferentially to route 6, and lactic acid and saccharinic acids predominate in the product,... 

Bode and co-workers have demonstrated the application of such substrates in a number of reactions, including cyclopentene ring formation and y-lactamisation [15]. For example, y-lactamisation to give 56 with saccharin-derived sulfonylimines 54 was achieved from a-hydroxyenone 53 with moderate to excellent stereocontrol (Scheme 12.10). 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

Figure 11.5 Formation of methylated saccharinic acids from glucose and cellulose, and methylated deoxyglucaric acid from glucuronic acid [66,681...

Mechanistic studies carried out in the course of recent years indicated that sodium saccharin may be involved in the formation of specific proteins occurring in rat urine which may contribute to the formation of bladder tumours. Most scientists and regulatory authorities now share the view that the incidence of bladder tumours in male rats after saccharin ingestion is species-specific and therefore probably without any significance for humans. Accordingly, the former temporaiy ADI of 0-2.5 mg/kg of body weight has been raised to 0-5 mg/kg by JECFA21 and the SCF.22... 

Saccharinic acid formation has been studied for several years. The four-step reaction proceeds rapidly in alkaline solution because of basic catalysis, particularly in the last two steps. Initially formed is an enediol that can undergo j8-elimination of a functional group, usually a hydroxyl group. The final two steps involve tautomerization to an a,j8-dicarbonyl intermediate followed by a benzilic acid rearrangement. This sequence is shown in Scheme 6 for the formation of the a- and j8 -xylometasac-charinic acids (30) by way of 3-deoxy-D-g/ycero-pentos-2-ulose (29). 

Because a benzilic acid rearrangement is the last step in the formation of saccharinic acids the difference between these results could be due to complexation of hydroxyl groups and alkoxide anions by the divalent calcium ions. Such a complexation apparently promotes isomerization and, hence, a fragmentation-recombination to the xylosaccharinic acid. This route has been questioned, and yet it provides a rational explanation of the results. 

This stopping or stabilization reaction with cellulose was presumed to involve a saccharinic acid rearrangement of the reducing group on the terminal D-glucose residue. This mechanism was confirmed by the formation of D-glucometasaccharinic acid, which still remained attached as the terminal unit (73). The stopping reaction is presented in Scheme 13. 

The enthalpy of formation of the corresponding sulfonamide (more commonly known as the artificial sweetener, saccharin) has also been measured, M. A. R. Matos, M. S. Miranda, V. M. F. Morais and J. F. Liebman, Mol. Phys., 103, 221 (2005). 

The formation of saccharinic acids125 isomeric with the reacting carbohydrate has long been known to occur by the following reaction... 

This benzilic acid type of rearrangement is the result of the action of alkali on the dicarbonyl compound, and is accelerated by calcium ions. The formation of saccharinic acids by the action of aqueous alkali on sugars is very well known 82,84,92 however, if ammonia is present, very little8 or no production of saccharinic acid has been reported. The reaction of the intermediate carbonyl compounds with ammonia is faster than the benzilic acid type of rearrangement to give saccharinic acid, and, hence, substituted imidazoles are formed, as illustrated in Scheme 9. 

Komoto detected lactic acid in the mixture from reaction of D-glucose with ammonia,4 and presumed that it was produced from pyruvaldehyde formed by decomposition of D-glucose. Lactic acid has, indeed, been found as a product of the action of alkali (lime-water) on substituted D-glucose and substituted D-fructose,81,83,96 and the mechanism of its formation involves the reversible aldol reaction, followed by formation of pyruvaldehyde, and the benzilic acid rearrangement already described for saccharinic acid this is illustrated83,96 in Scheme 11. 

ML Puttemans, L Dryon, DL Massart. Extraction of organic acids by ion-pair formation with tri-n-octylamine. Part V. Simultaneous determination of synthetic dyes, benzoic acid, sorbic acid and saccharin in soft drinks and lemonade syrups. J Assoc Off Anal Chem 67(5) 880-885, 1984. 

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