Saccharinic acids isomerization

Aldoses generally undergo benzilic acid-type rearrangements to produce saccharinic acids, as well as reverse aldol (retro-aldol) reactions with j3-elimination, to afford a-dicarbonyl compounds. The products of these reactions are in considerable evidence at elevated temperatures. The conversions of ketoses and alduronic acids, however, are also of definite interest and will be emphasized as well. Furthermore, aldoses undergo anomerization and aldose-ketose isomerization (the Lobry de Bruyn-Alberda van Ekenstein transformation ) in aqueous base. However, both of these isomerizations are more appropriately studied at room temperature, and will be considered only in the context of other mechanisms. 

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. 

The saccharinic acids formed from hexoses have been especially examined because of the relationships of the a and /8 isomers (C-2 epi-mers). Structures of saccharinic acids derived from D-glucose are glu-cometasaccharinic acid (51), glucoisosaccharinic acid (52), and glucosaccharinic acid (53). The a- and /3- isomers of metasaccharinic acid can reversibly isomerize when exposed to base because of the labile proton at C-2. 

It has been postulated (37) that lactulose is formed from lactose by the Lobry de Bruyn and Alberda van Ekenstein transformation, whereby glucose is isomerized to fructose via an enol intermediate. In turn, two mechanisms have been proposed for the degradation of this intermediate (38)- One involves the addition of a proton to the enediol resulting in epimeric aldoses and the original ketose, while the other involves 8-elimination to yield galactose and saccharinic acids. The authors experimental data would tend to better support the second pathway. 

Three structurally isomeric forms have been established for the six-carbon saccharinic acids. In the order of their discovery, these are the sac-charinic or 2-C -methylpentonic acids, the isosaccharinic or 3-deoxy-2-C -(hydroxymethyl)-pentonic acids, and the metasaccharinic or 3-deoxy-hexonic acids. Although none of these six-carbon, deoxyaldonic acids has been crystallized, six are known in the form of crystalline lactones (saccharins). All the possible metasaccharinic acids of less than six-carbon content have been obtained, in the form of crystalline derivatives, by the sugar-alkali reaction. Only one example of a branched-chain deoxyaldonic acid (the racemic, five-carbon isosaccharinic acid) of other than six-carbon content has been so obtained. The formation of saccharinic acids containing more than six carbon atoms remains to be explored. 

Shortly after the discovery of Peligot s a -D-glucosaccharin, Dubrun-faut reported that the calcium salt of a monobasic acid resulted from the action of lime-water on maltose. Cuisinier named the acid isosaccharinic acid, after he had prepared from it a crystalline lactone (CeHioOt) isomeric with Peligot s a -D-glucosaccharin. The name was expanded to a -D-iso-saccharinic acid after Nef obtained evidence of the concurrent formation of its epimer, /3 -D-isosaccharinic acid, in the hexose-alkali reaction. 

The epimerie D-glucometasaccharinic acids were first isolated by Nef from the interaction of n-glucose and hot, concentrated sodium hydroxide. D-Glucose is isomerized and smoothly degraded under these conditions to a mixture of saccharinic acids, in a yield of over 80%. 

D-glucosaccharinic acid but also D-isosaccharinic acid and Kiliani s para-saccharinic acid might be formed by recondensation of appropriate alde-hydic fragmentation products with a lower-carbon metasaccharinic acid. He proposed that the unbranched metasaccharinic acids, in contrast, are formed by direct dismutation of the isomeric sugars. 

Nef s theory of the mechanism of formation of the saccharinic acids is outlined, in its original form, in a paper published in 1907 and, in its final form, in his comprehensive article of 1910. The theory proposes that the reaction takes place in two major steps (a) the isomerization of the sugar, with loss of water, to an a-dicarbonyl compound, and (b) a benzilic acid type of rearrangement of the latter, with hydration, to the saccharinic acid. The second step involves chain rearrangement in the production of the saccharinic, isosaccharinic, and Kiliani s parasaccharinic acids, but not in the production of the metasaccharinic acids. 

According to the theory, the initial reaction is the formation of an alk-oxide (I) between the base and the sugar hydroxyl group vicinal to the carbonyl group. A molecule of base is then eliminated, to give the free, methylenic intermediate (II). The latter isomerizes to the epoxy compound (III) and thence to the a-dicarbonyl intermediate (IV). Finally, a benzilic acid type of rearrangement, with hydration and dismutation, gives the saccharinic acid. 

The successive isomerization of an aldose to a 2-ketose and then to a 3-ketose was explained by assmning the intermediate formation of 1,2- and 2,3-enediols. Thus, a single aldose, under the influence of alkali, could produce all three types of saccharinic acid. 

The general statement of the isomerization mechanism, as given in the opening paragraph of this Section, is accepted at the present time as a mechanism of saccharinic acid formation. However, Nef s concept of the mode of isomerization of the original sugar to the intermediate a-dicarbonyl compound has undergone radical revision. 

No detailed investigation of the acids has so far been made, but paper-chromatographic and electrophoretic studies indicated a mixture containing one preponderant component which was, itself, probably a mixture of the expected, isomeric, cyclic saccharinic acids. One of the minor neutral compounds present was crystalline and, in contrast to the preponderating... 

This work on the isomerization of D-glucose was responsible for the intensive interest which Sowden developed in saccharinic acids. From Schaffer s work, Sowden learned of the relative ease of isolation of saccharinic acids from isoraerized solutions. As a result, Miss Dorothy J. Kuenne was started on an investigation of the mechanism of formation of saccharinic acids, and the first report of this work was published in 1953. In the next few years, six additional investigations were reported in which specially labeled sugars played an important role. To Volume 12 of this Series, Sowden contributed a review on saccharinic acids which presents a clear and impressive account of the state of this complex area of sugar chemistry. 

Heat treatment of alkaline solutions (pH >12) at >110 °C causes splitting of the glucosidic linkage, isomerization, enolization and destruction to C3-and C2-compounds D,L- lactic acid, acetic acid, saccharinic acids or the corresponding aldehydes. Further aldolic condensation leads to - caramel color. 

Piroxicam Piroxicam, 1,1 -dioxid-4-hydroxy-2-methyl-iV-2-pyradyl-2//-1,2-benzothiazine-3-carboxamide (3.2.78), is synthesized from saccharin (3.2.70). Two methods for saccharin synthesis are described. It usually comes from toluene, which is sulfonated by chlorosulfonic acid, forming isomeric 4- and 2-toluenesulfonyl chlorides. The isomeric products are separated by freezing (chilling). The liquid part, 2-toluenesulfonyl chloride (3.2.68) is separated from the crystallized 4-toluenesulfochloride and reacted with ammonia, giving 2-toluenesul-fonylamide (3.2.69). Oxidation of the product with sodium permanganate or chromium (VI) oxide in sulfuric acid gives saccharin—o-sulfobenzoic acid imide (3.2.70) [123-126]. 

A major distinction for nucleophilic reactions with ambident anions is whether they proceed with kinetic or thermodynamic control.80 N-Substituted saccharins (10) should be thermodynamically more stable because of amide character than the isomeric pseudosaccharin (3) of imidate structure. In fact 3 may be rearranged thermally to 10 in an irreversible reaction.96 The threshold for thermodynamic control appears to be lowered for electrophiles with multiple bonds, e.g., formaldehyde, reactive derivatives of carboxylic acids, but also quaternary salts of N-heterocyclic compounds.80 It will be seen that in those cases substitution indeed occurs at the nitrogen, not necessarily through thermodynamic control. 

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