Studies on Prototropic Tautomerism in Neutral and Monoanionic Forms of Pyrimidines by Nuclear Magnetic Resonance Spectroscopy

Abstract

Pyrimidines, Prototropic Tautomer Populations, Nuclear Magnetic Resonance, 1H and 13C Chemical Shifts, 1H, *H Coupling Constants NMR methods have been applied to evaluation of prototropic tautomerism, N (1 )H ^ N (3) H. in several selected pyrimidines, viz. the neutral forms of isocytosine and 2-alkylthiopyrimidone-4, and the monoanionic forms of uracil, 5-fluorouracil and 4-thiouracil.The predominant tautomeric species of the neutral forms could be estimated only qualitatively from chemical shifts. For the monoanionic forms this procedure was not applicable, for reasons which are discussed in detail.For the monoanionic form of uracil, 13C chemical shifts of C(5) provided a suitable criterion for quantitative estimation of the populations of the two known tautomeric species. However, the potential scope of this procedure appears somewhat limited.By contrast, the values of the vicinal proton-proton coupling constants, /(5 ,6 ), provided both necessary and adequate criteria for quantitative evaluation of the tautomer populations for all the neutral and monoanionic forms. The results were in satisfactory agreement with those obtained by optical spectroscopic methods. In some instances the results obtained in this way may be more reliable than those derived from optical methods.The range of applicability, and utility, of NMR methods to studies on protropic tautomerism in pyrimidines are critically assessed.Considerable attention has been devoted to in vestigations on the tautom erism of natural purines and pyrimidines, and of many of their analogues, to a large extent because of the biochemical and genetic significance of this phenomenon. A good deal of the inform ation in this field has been derived with the aid of UV and IR s p e c t r o s c o p y , extensively reviewed by Elguero et a l.1, and most widely applied in solution studies 2-4. Investigations on such tautomerism in the gas phase, and their relevance to solution studies, have been recently reviewed by B eak5. NMR methods have also been applied, with particular utility in studies on ketoenol and amino-imino tautom erism of such com pounds as uracil, cytosine, and some of their deriv atives and nucleosidesln 6~8. Additional develop ment include the use of 13C chemical shifts for evaluation of tautomer populations in purines and purine nucleosides9' 10, and of 15N chemical shifts Requests for reprints should be sent to R. Stolarski, De partment A b b revia tio n s: UV, ultraviolet; IR, infrared; NMR, nuclear magnetic resonance; DMSO, dimethyl sulfoxide; DSS, sodium 2,2 dimethyl, 2 silapentane sulfonate; TMS, tetramethylsilane. Scheme 1. Prototropic tautomeric equilibria N (1) -H^ N (3) -H in monoanionic (upper) and neutral (lower) forms of pyrimidines. The N (1) -H tautomers are shown at the left and the N (3) -H tautomers to the right. R = H or F, X = 0 or S, Y = N H , or alkylthio.

Tautomerism of pyrimidine bases—uracil, cytosine, isocytosine: Theoretical study with complete optimization of geometry

“…This result is consistent with available experimental data since it is known that the population of IIIb increases from about 50% in aqueous medium to 100% in apolar solvents [33]. It has been demonstrated by uv spectroscopy that IIIb predominates in the gas phase (Nasierowski, unpublished results).…”

“…The C N D O /~ method is not capable to predict correctly the most stable tautomer. Moreover, in both the latter methods, contrary to the experimental evidences from the gas phase [2,10] and apolar solvents [32,33], the forms with fully aromatic structure of the pyrimidine ring If, IIf, IIIf are heavily favored. What is more, the energy differences are so large that the predominance of the other forms in solution, contrary to previous suggestions [25], cannot be attributed to the differences in the solvation energy.…”

Principles of Nucleic Acid Structure

“…graphic methods [summarized in (429); for newer work see (430)(431)(432)(433)] and quantum chemical methods (179,180). The essential results can be summarized with a few sentences.…”

Structure and Stability of Chemically Modified DNA Bases: Quantum Chemical Calculations on 16 Isomers of Diphosphocytosine

“…The five nucleic acid bases, cytosine, thymine, uracil, adenine, and guanine, found in DNA and RNA control the replication of DNA, store information required to synthesize proteins, and translate this information to the protein. Tautomerism is a well-known phenomenon occurring in nucleic acid bases [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16], in which proton transfer from the heterocyclic ring center to an exocyclic oxo-or imino-group leads to the formation of either an -OH or an -NH 2 groups. These processes are known as keto-enol or imino-amino tautomerism, respectively.…”