Uric acid Tautomerism

Triamterene (31) is a diuretic that has found acceptance because it results in enhanced sodium ion excretion without serious loss of potassium ion or significant uric acid retention. Tautomerism of aminopyrimidines (e.g., 27a and 27b) serves to make the "nonenolized" amine at the 5 position more basic than the remaining amines. Thus, condensation of 27 with benzaldehyde goes at the most basic nitrogen to form 28. Addition of hydrogen cyanide gives the a-aminonitrile (29). Treatment of that intermediate with base leads to the eyelized dihydropirazine compound (30). This undergoes spontaneous air oxidation to afford triamterene (31). ... 

The amino groups are replaced with oxygen. Although here a biochemical reaction, the same can be achieved under acid-catalysed hydrolytic conditions, and resembles the nucleophilic substitution on pyrimidines (see Section 11.6.1). The first-formed hydroxy derivative would then tautomerize to the carbonyl structure. In the case of guanine, the product is xanthine, whereas adenine leads to hypoxanthine. The latter compound is also converted into xanthine by an oxidizing enzyme, xanthine oxidase. This enzyme also oxidizes xanthine at C-8, giving uric acid. 

The nucleoside formed from hypoxanthine and ribose is known as inosine (Ino or I) and the corresponding nucleotide as inosinic acid. Further substitution at C-2 of -H by -OH and tautomerization yields xanthine (Xan). Its nucleoside is xanthosine (Xao, X). A similar hydroxylation at C-7 converts xanthine to uric acid, an important human urinary excretion product derived from nucleic acid bases. 

Figure 10.2 Tautomeric forms of uric acid. Although uric acid does not occur in nucleic acids (it is a degradation product of adenine and guanine), the tautomeric structures observed here are typical of all purine bases of this type. At pH 7, the keto forms predominate.

The system was first named by Fischer 0899CB435) but the correct ring structure was proposed much earlier <1875LA( 175)243) in a formula for uric acid. In the general literature purine nomenclature has been to a large extent affected by the abundance of trivial names for compounds which were isolated before their structures were known and by variation in description of tautomeric forms. 

The assigning of the two types of formulas in some cases, Le.j the hydroxyl or alcohol formula (enol formula) and the ketone or carbonyl formula ketone formula), is due to the fact, not mentioned in the case of uric acid, that it is probably a tautomeric compound... 

As shown in the above formulas uric acid exists in tautomeric forms, having the constitution either of a hydroxyl compound, enol form, or of a ketone, keto form. The purine alkaloids which we have mentioned are similar hydroxyl or amino derivatives of purine. As tautomeric compounds they also exist in the two forms. Those which contain hydroxyl groups have the enol and the keto forms, while, if they contain ammonia residues instead of hydroxyl, they have the corresponding amino or imino forms. In the following formulas only one tautomeric form will be given, viz., the keto and the amino. 

Structures of tautomeric forms of uric acid. In the lactim form, uric acid has two acidic hydrogens, with pK values of 5.75 and 10.3. At physiological pH (7.4), the predominant species of the lactim form is urate monoanion. 

In many of the nitrogen-containing rings, the hydrogen can shift to produce a tautomer, a compound in which the hydrogen and double bonds have changed position (i.e., -N=C-OH—>-NH-C=0) (Fig. 5.26). Tautomers are considered the same compound, and the structure may be represented either way. Generally one tautomeric form is more reactive than the other. For example, in the two tautomeric forms of uric acid, a proton can dissociate from the enol form to produce urate. 

Fig. 5.26. Tautomers of uric acid. The tautomeric form affects the reactivity. The enol form dissociates a proton to form urate.

It is probable that a number of substitution-products of uric acid are derived from a tautomeric form of the acid. It will be recalled that there is evidence for the view that certain... 

With certain reagents, for example phosphorus oxychloride, uric acid acts in a manner which indicates that it has the tautomeric configuration —... 

Melamine (2,4,6,-triamino-1,3,5-triazine) is obtained by trimerization of cyanamide or commercially by thermal cyclocondensation of urea at 400°C with elimination of NH3 and CO2. Polycondensation of melamine with formaldehyde produces melamine resins that are used as plastics, glues and adhesives. Cyanuric acid 15 (2,4,6-trihydroxy-1,3,5-triazine) was obtained by Scheele (1776) from pyrolysis of uric acid and was the first 1,3,5-triazine derivative known. Cyanuric acid is synthesized by trimerization of isocyanic acid and is tautomeric with isocyanuric acid 16 ... 

Uric acid [7,9-dihydro-l//-purine-2,6,8(3f0-trione and tautomeric forms]. 

As is well known, the two purines, adenine and guanine, originating from nucleic acids or from high-energy phosphate compounds like ATP or GTP, are catabolized in man to uric acid. The intermediately formed hypoxanthine and xanthine are both oxidized to uric acid by the enzyme xanthine oxidase. This enzyme introduces an oxygen atom between the carbon and hydrogen atom in position Cg. Of the two tautomeric forms of uric acid, the amido (lactam) and the imido (lactim) forms, the latter has a more acid character. 

There is evidence that the first product of uricase oxidation is not HDC, but an unknown compound which contains the same number of carbon atoms as uric acid 266-269). HDC and the unknown compound had different ultraviolet absorption spectra the unknown compound was quite unstable and yielded allantoin more readily than HDC. It is possible that this unknown compound (X) had the structure shown in Fig. 14, and that it is converted to allantoin without preliminary hydration to HDC 261). Although X per se is not symmetrical, a tautomeric shift of the double bond to the other ring would result in equivalent structures and explain the equal labeling found in both the urea and hydantoin moieties of allantoin derived from uric-1,3-Ni acid 202). However, hydration of X at the 3 4 double bond could have also produced HDC, which would be converted subsequently to allantoin. Thus, both X and HDC might have been intermediates in the oxidation of uric acid. 

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