Pyrimidine tautomeric form

These relationships are general Hydroxyl substituted purines and pyrimidines exist in their keto forms ammo substituted ones retain structures with an ammo group on the ring The pyrimidine and punne bases m DNA and RNA listed m Table 28 1 follow this general rule Beginning m Section 28 7 we 11 see how critical it is that we know the cor rect tautomeric forms of the nucleic acid bases... 

MO studies (AMI and AMI-SMI) on the tautomerism and protonation of 2-thiopurine have been reported [95THE(334)223]. Heats of formation and relative energies have been calculated for the nine tautomeric forms in the gas phase. Tire proton affinities were determined for the most stable tautomers 8a-8d. Tire pyrimidine ring in the thiones 8a and 8b has shown a greater proton affinity in comparison with the imidazole ring, or with the other tautomers. In solution, the thione tautomers are claimed to be more stabilized by solvent effects than the thiol forms, and the 3H,1H tautomer 8b is the most stable. So far, no additional experimental data or ab initio calculations have been reported to confirm these conclusions. 

Moreover, with a change of solvent, a new tautomeric form can arise owing to formation of intermolecular hydrogen bonds in place of the previously existent intramolecular hydrogen bonds. This situation is characteristic, for example, for pyrimidine derivatives 49, for which the use of polar (DMSO, DMF, MeOH, HMPT) solvents or specifically solvating cosolvents (S) (e.g., a small amount of water or A-methylpyrrolidinone) leads to the appearance of ylidene tautomer 49b with the p-quinonoid disposition of the double bonds (Scheme 18) [88KGS521 90UK457]. 

The tautomerisation of the purine bases adenine and guanine and of the pyrimidine bases thymine, cytosine, and uracil has important implications in molecular biology, and the occurrence of rare tautomeric forms of these bases has been suggested as a possible cause of spontaneous mutagenesis (Lowdin, 1965 Pullman and Pullman, 1971 Kwiatowski and Pullman, 1975). Three of the most likely tautomers for cytosine are shown in [87]—[89], together with the less likely imino forms [90] and [91] (Scanlan and Hillier,... 

Some of the impetus for studying tautomeric equilibria in heterocycles arises because of the postulate that point mutations in genetic material may be introduced when a given base exists in a tautomeric form during replication [279, 305-307], Cytosine, in particular, has imino and hydroxy tautomers that are within 3 kcal/mol of the global minimum illustrated above (because of the very large number of possible tautomers for the purines and pyrimidines, only the lowest energy tautomers are presented). This analysis has been made based on a... 

Kleinpeter et al. carried out ab initio and semi-empirical (PM3) calculation in order to rationalize the tautomeric equilibria of 7-hydroxy-5-methyl[l,2,4]triazolo[l,5- ]pyrimidine <1995JST(335)273, 1997JST(435)65>. This compound can exist in four tautomeric forms a-d (Figure 1). The authors concluded that the high computational level available can sufficiently reproduce the position of tautomeric equilibria in solution and, thus, can serve as a useful tool instead of time-consuming experimental studies. 

Figure 1 Tautomeric forms of 7-hydroxy-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine.

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. 

Oxo-4-amino-l,2,5,6-tetrahydro-lf/-pyrimidine. A dihydropyrimidine, not a tetrahydropyrimidine (two exo- and endoeyclic double bonds) 4-Amino-5,6-dihydro-2(l//)-pyr>midone (Chem. Abstr.) assigns the correct oxidation state, tautomeric form and location of the proton the danger is that the latter is not always known, however. 

We should note particularly that uracil and thymine are dioxypyrimidines, whereas cytosine is an amino-oxypyrimidine. All three pyrimidines are thus capable of existing in several tautomeric forms (see Section 11.6.2). 

The bases are monocyclic pyrimidines (see Box 11.5) or bicyclic purines (see Section 11.9.1), and all are aromatic. The two purine bases are adenine (A) and guanine (G), and the three pyrimidines are cytosine (C), thymine (T) and uracil (U). Uracil is found only in RNA, and thymine is found only in DNA. The other three bases are common to both DNA and RNA. The heterocyclic bases are capable of existing in more than one tautomeric form (see Sections 11.6.2 and 11.9.1). The forms shown here are found to predominate in nucleic acids. Thus, the oxygen substituents are in keto form, and the nitrogen substituents exist as amino groups. 

Four NH-tautomeric forms are possible for pyrazolo[3,4-d]pyrimidine (3-6). In the solid state as well as in neutral media this compound was shown to exist as 3. In basic media, the mesomeric anion 300 is the predominant species. In acidic solutions, 301 predominates as the monocation (58JCS2973). 

Neutral 4-aminopyrazolo[3,4-d]pyrimidines exists in water in two tautomeric forms 1//-4-amino (1H4APP) and 2//-4-amino (2H4APP) isomers (X = 2H4APP/1H4APP = O.I at lOO C and OH tautomerization = 9.0kcal mol ). Interconversion of the two forms is catalyzed by and OH through either an intermediate cation common to both tautomers or through an intermediate anion. 

With respect to (75) the possible mesomeric structures are given in Scheme 5. A few remarks will be placed here regarding possible mesomeric or tautomeric structures for the other species depicted in Scheme 3. For all one- or two-electron reduced species various tautomeric forms can exist, e.g. iminol tautomers. Such tautomers do not exist in flavoquinone. In addition, in (76) and (79) the negative charge could also be placed on the other hetero atoms in the pyrimidine subnucleus... 

FIGURE 8-9 Tautomeric forms of uracil. The lactam form predominates at pH 7.0 the other forms become more prominent as pH decreases. The other free pyrimidines and the free purines also have tautomeric forms, but they are more rarely encountered. 

X-Ray results are available for the molecular structures of nearly all rare pyrimidine constituents of the nucleic acids except for isothiocyto-sine. Thio analogs of uracil exist in the tautomeric form of the 32 type ... 

In Sections II and IV we have described the application of NMR and NQR spectroscopy to the determination of the localization of mobile protons of the pyrimidine bases and for the prediction of the tautomeric structures of these molecules. Here, we shall describe the application of these spectroscopies to the elucidation of the electronic structures of the most stable tautomeric forms of the bases. 

The tautomerism of pyrimidines was discussed in Chapter 2, Section A,6. The tautomeric forms shown in Fig. 5-1 predominate. However, it is possible that minor tautomers such as the following are sometimes preferentially bound into active sites of enzymes where the dielectric... 

Mass fragmentation of modified nucleobases of 6-methyl tetrazolo[l,5-c]pyrimidin-5(6fl)-one and its 7 and 8-methyl derivatives suggested the occurrence of both azide and tetrazole tautomeric forms of M (661 and 662). For the 8-halo derivatives, only the of the tetrazole form was proposed (930MS643) (Scheme 135). 

The 9-benzoyl- and 9-[(ethoxycarbonyl)carbonyl]tetrahydro-4//-pyrido[l,2-a]pyrimidin-4-ones also exhibit predominantly the 1,6,7,8-tetrahydro tautomeric forms in solution [85JHC593 89JCS(P2)1613]. 

It has been shown [248] that unsubstituted dihydropyrimidine 427 existed in tautomeric form D. But introduction of phenyl substituents at positions 2 and 4 leads to a convergence of energies of the tautomeric forms and 4,6-diphenyl-l,2(2,5)-dihydropyrimidine is observed in solutions of CDC13 as a mixture of D and E in a ratio of 2 1 [248]. Pyrimidines 427 containing electron-donors at positions 4 and 6 exist in the dihydro form E [424]. 

The problem of tautomeric equilibriums in annelated 1,5-diazepines was studied in [68] by means of NMR spectroscopy, X-ray analysis and quantum-chemical calculations. It was shown that the electron-withdrawing rings (e.g., pyrimidine moiety) fused with the diazepine cycle increase the stability of the antiaromatic enamine tautomeric forms A and C, while in the case of benzodiazepine, a diimine tautomer B was found to be the most stable. Ab initio quantum-chemical calculations and NMR spectroscopic data showed that solvation of seven-membered heterocycles with polar solvents contributes considerably to the stabilization of the enamine forms A and C. This assumption was also proven by X-ray analysis, which showed that in the solid state these diazepines exist in the diimine form B. 

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