4- Hydroxypyrimidine, tautomerism

O-Methyl and O-benzyl ethers of hydroxyurea have been used for the synthesis [23] of iV -hydroxypyrimidines (tautomeric with pyrimidine-Moxides) as shown in Fig. 10.10. 

Repeat your analysis for tautomeric equilibria between 4-hydroxypyridine and 4-pyridone, 2-hydroxypyrimidine and 2-pyrimidone and 4-hydroxypyrimidine and 4-pyrimidone. For each, identify the favored (lower-energy) tautomer, and then use equation (1) to calculate the ratio of tautomers present at equilibrium. Point out any major differences among the four systems and rationalize what you observe. (Hint Compare dipole moments and electrostatic potential maps of the two pyridones and the two pyrimidones. How are these related to molecular stability )... 

Hydroxypyrimidine (89a) can tautomerize to two alternative 0X0 forms, 90 (R = H) and 91 (R = H). The infrared solution spectra of pyrimidin-2- and -4-one clearly indicate the presence of both C=0 and NH groups, and by using these spectra Mason demonstrated that pyrimidin-4-one existed predominantly in the o-quinonoid... 

Since a knowledge of the correct tautomeric form of the pyrimidines is a requisite for understanding the mode of binding to active sites, as well as nucleic acid structure and modification, the formulae of the conventionally-named 2- and 4-hydroxypyrimidines are presented in the correct lactam, or pyrimidone, form in this chapter. Other physical properties of the pyrimidines, such as dissociation constants, protonation sites, and distribution coefficients, are presented in cases where there is a known relation to drug activity. Biogenesis and enzyme control mechanisms are discussed where they relate to an understanding of inhibitor action. 

We also enconnter tautomerism in hydroxy- and amino-diazines, and the preference for one tautomeric form over the other follows what we have seen with the pyridine derivatives. Thus, with the exception of 5-hydroxypyrimidine, all the mono-oxygenated diazines exist predominantly in the carbonyl tan-tomeric form. We term these amide-like tautomers diazinones. 5-Hydroxypyrimidine is analogous to 3-hydroxypyridine, in that the hydroxyl is wrongly positioned for tautomerism. 

Both 2- and 4-hydroxypyrimidine can exist in both hydroxyl and keto tautomeric forms, and the proportion of each is highly dependent on the state of the molecule. In the gas phase 2-hydroxypyrimidine 20 exists primarily in the hydroxy form, whereas the 4-isomer 21 exists predominantly in the oxo form <2006AHC(91)1>. Solvation tends to shift the equilibrium toward the oxo form for both isomers <2006AHC(91)1>. 

Extra nitrogen heteroatoms in the ring provide alternative sites for the tautomeric proton. 4-Hydroxypyrimidine, for instance, can exist as such (92), or in the 1H- (93) or 3H- (94) pyrimidone... 

Hydroxypyrimidine can potentially exist in two tautomeric forms 48a and 48b (three isomers are possible for unsymmetrically substituted 2-hydroxypyrimidines), whereas three potential tautomers 49a, 49b, and 49c could be involved into tautomeric interconversions of 4-hydroxypyrimidine. As in many (especially, early) reports, the exact form for the oxo tautomer of 4-hydroxypyrimidine was not identified, it will be referred just as oxo tautomer. 

The 3/(ch) values for the C-N-CH, C N = CH, and C = N-CH structural elements were used as a valuable criterion for differentiating aromatic from non-aromatic structures and applied for tautomerism studies in 4-hydroxypyrimidines (83OMR20). 

When OH is placed at the 5-position, tautomerism is not important, and the normal phenol-hke acidity is present. Thus, the pKa of 5-hydroxypyridine is 6.78. This compound is therefore a stronger add than 3-hydroxypyrimidine with pKa 8.72, the result of the second C=N unit adding to the electron-withdrawing anion stabilizing effect. 

O-Alkylation of hydroxypyrimidines. Hydroxypyrimidines (la), which exist in equilibrium with the tautomeric forms (lb) and (Ic), undergo selective O-alkylation with Mccrwein s reagent. ... 

These compounds exist in several tautomeric forms. As a rule, hydroxypyrimidines prefer the lactam form, aminopyrimidines, however, the enamine form. 

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