Cytosine, tautomerism

For a discussion of tautomerism involving the carbonyl group of cytosine, see Section II,M.)... 

Pyridones and other six-membered compounds (functional tautomerism). The pyridone /hydroxypyridine tautomerism (76AHCS1, p. 87), especially 2-pyridone (15a)/2-hydroxypyridine (15b), has received more attention from theoreticians than any other example of tautomerism, probably in part because it is a simple model for biologically important molecules such as thymine, cytosine, and uracil (Scheme 8). 

Uracil, thymine, and cytosine have been studied using this technique (89JA2308 and references therein). For uracil and thymine, the dioxo tautomer predominates in the case of cytosine (70), three tautomers were detected, 70a, 70b, and 70c, the last one being the least abundant. The gas-phase tautomeric equilibrium of 2-pyridone 15a and 2-hydroxypyridine 15b has been studied by MW spectroscopy (93JPC46) using both a conventional spectrometer and a jet-cooled millimeter-wave spectrometer. The relative abundances are 3 1 in favor of the hydroxy form 15b, which exists in the Z conformation shown (Scheme 23). 

Sobolewski AL, Domcke W, Hattig C (2005) Tautomeric selectivity of the excited-state lifetime of guanine/cytosine base pairs The role of electron-driven proton-transfer processes. Proc Natl Acad Sci USA 102 17903-17906... 

Estrin, D. A., L. Paglieri, and G. Corongiu. 1994. A Density Functional Study of Tautomerism of Uracil and Cytosine. J. Phys. Chem. 98, 5653. 

Hall, R. J., N. A. Burton, I. H. Hiller, and P. E. Young. 1994. Tautomeric equilibria in 2-hydroxypyridine and in cytosine. An assessment of density functional methods, including gradient corrections. Chem. Phys. Lett. 220,129. 

In 1 JMSO-z4, or DMF-(/, the 1 1 condensation products of cytosine or iV-methylcytosine with triformylmethane, compounds 39a and 39b, showed ring-chain tautomerism with the ring-closed products 40a and 40b (see Equation (2), Section 12.04.2.4) <1996ACS1137>. 

Ring-chain tautomerism of the uracils 297 and cytosines 299 (R = H, Me) to the respective pyrimido[6,l-3][l,3]oxa-zines 298 and 300 takes place in CD3OD/DMSO-1S6 in the presence of Et3N or NaOD. Cfe-addition is predominant. 

The equilibrium between the amino and imino forms of cytosine has also been studied by Cieplak et al.9 Their results agree with those of Colominas et al. In this study, the related 2-oxopyridine and 2-oxopyrimidine molecules were also treated. In both these molecules the amine group of cytosine is not present, and in oxopyridine only one ring nitrogen is present. This enabled the keto-imino tautomerism to be studied in isolation. In both cases the imino form dominates in the gas phase, but the keto form is stabilised by solvation, and dominates in solution, in agreement with experiment. 

C. Colominas, F. J. Luque, and M. Orozco, Tautomerism and protonation of guanine and cytosine. Implications in the formation of hydrogen-bonded complexes, J. Am. Chem. Soc. 118 6811 (1996). 

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... 

Tautomerism is responsible for genetic mistakes and for the whole concept of genetic evolution. As an example, cytosine in its imino form pairs with adenine and thus acts as a mimic of uracil. Cytosine normally pairs with adenine, but tautomerism leads to a mutation (Scheme 17).1... 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

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. 

Tautomeric structures of adenine, guanine, cytosine, thymine and uracil are—... 

The Mg+ complexes of cytosine, thymine and uracil are the most complex system studied via photodissociation spectroscopy to date . A complication for these systems is that these nucleobases can exist in various tautomeric forms and that complexation of a metal can change the stability order of the tautomers. DFT calculations located four tautomeric Mg(cytosine)+ complexes, and three of these (29, 30, and 31) were suggested to be responsible for the four reactive photofragment ions 32-35 observed at a wavelength of 360 nm (Scheme 4) . Related photofragmentation reactions were observed for the Mg(thymine)+" and Mg(uracil)+" complexes . ... 

Before the polymerase moves on, the cytosine undergoes a tautomeric shift from C to C. The new nucleotide is now mispaired. 

The principal tautomeric properties of the fundamental biological pyrimidines—cytosine, uracil, and thymine—are due to the presence in these N-heteroaromatic compounds of electron-donor substituents such as NH2 and OH and of SH in some important analogs. The labile hydrogen may remain attached at the exocyclic 0, N, or S atom or migrate to one of the ring nitrogens, giving rise to three principal types of tautomerism (Scheme 1) ... 

In general, the problem of tautomerism in nucleic acid bases has been approached by comparing the IR spectra of several isoelectronic model compounds. The model corresponding to the cytosine tautomers 4 or 5 have not yet been investigated. The IR spectroscopy studies cannot therefore definitely rule out these tautomers. It seems, however, that they do rule out form 6 for cytosine and cytidine and indicate that the dominant tautomer of the compounds in aqueous solution is the lactam-amino form 2, and that the protonated cations have the structure 7. 

The first PMR spectra57,58 attributed the tautomeric structure (7) to the cation of cytosine, in agreement with X-ray studies and IR data. For the preferred neutral form of cytosine in solution Kokko et al.59... 

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