In uracil

The aromaticity of the pyrimidine and purine ring systems and the electron-rich nature of their —OH and —NHg substituents endow them with the capacity to undergo keto-enol tautomeric shifts. That is, pyrimidines and purines exist as tautomeric pairs, as shown in Figure 11.6 for uracil. The keto tautomer is called a lactam, whereas the enol form is a lactim. The lactam form vastly predominates at neutral pH. In other words, pA) values for ring nitrogen atoms 1 and 3 in uracil are greater than 8 (the pAl, value for N-3 is 9.5) (Table 11.1). 

Experimentally the lowest peak in uracil corresponding to the bright nn states is observed in the gas phase at 5.1 eV [132], In thymine the first band maximum is at 4.8 eV [132], An extended table of available experimental results taken from absorption spectra and circular dichroism is given by Roos and coworkers [125] for both molecules. 

Figure 11-5. Energy level diagram of minima and conical intersections involved in the radiationless decay in uracil. Energies and structures taken from Ref. [147, 224]...

As discussed earlier, thymine is very similar to uracil in its excited states pattern. This is also true for its radiationless decay mechanism except from the fact that the excited state lifetime in thymine is somewhat longer than in uracil. Theoretically the mechanism for radiationless decay has been studied using CASPT2 electronic structure methods [150, 152],... 

The ab initio molecular dynamics study by Hudock et al. discussed above for uracil included thymine as well [126], Similarly to uracil, it was found that the first ultrafast component of the photoelectron spectra corresponds to relaxation on the S2 minimum. Subsequently a barrier exists on the S2 surface leading to the conical intersection between S2 and Si. The barrier involves out-of-plane motion of the methyl group attached to C5 in thymine or out-of-plane motion of H5 in uracil. Because of the difference of masses between these two molecules, kinematic factors will lead to a slower rate (longer lifetime) in thymine compared to uracil. Experimentally there are three components for the lifetimes of these systems, a subpicosecond, a picosecond and a nanosecond component. The picosecond component, which is suggested to correspond to the nonadiabatic S2/S1 transition, is 2.4 ps in uracil and 6.4 ps in thymine. This difference in the lifetimes could be explained by the barrier described above. 

Cytosine was the first nucleobase whose radiationless decay was studied with quantum mechanical methods. Nevertheless, its first excited states are not so clearly separated as in uracil and thymine, and this causes complications in the computational studies of the photophysics. So, many computational studies have been reported to elucidate the mechanisms for radiationless decay to the ground state but, not always with the same conclusions. 

Figure 11-16. Diagram of the energy levels at the two- and three-state conical intersections in uracil and adenine calculated at the MRCI level, ciIJK represents conical intersection between states Sj, S j, S -. (From Ref. [210])...

Shukla MK, Leszczynski J (2002) Phototautomerism in uracil a quantum chemical investigation. J Phys Chem A 106 8642... 

Marian CM, Schneidaer F, Kleinschmidt M, Tatchen J (2002) Electronic excitation and singlet-triplet coupling in uracil tatutomers and uracil-water complexes. Eur Phys J D 20 357... 

No increase in uracil or orotic acid Uracil and orotic acid increase in blood and urine... 

Ornithine transcarbamoyiase (increase in uracil and orotic acid)... 

Nucleic Base Acidities. The N1 and N3 Acidities of Uracil. Published in J. Am Chem. Soc. 2000, 122, 6258-6262. Our progress to date involves calculations and experiments for the determination of nucleobase activities. We have learned that there is an enormous difference in the inherent stabilities of anions at the N1 (7) and N3 (8) positions in uracil (3a, Figure 1). 

Nucleotide Uptake. When uracil labelled with tritium was supplied to 15-day-old ozone-treated cotton leaves, a 2-fold increase in uracil incorporation into the RNA fraction was observed (Table IV). In this one particular case, there appeared to be a greater percentage of uracil incorporation into RNA in treated tissue than in control tissue. 

The fluorine atom can be present in position 5 in uracil derivatives, or in position 1 in that of purine, as in fludarabine, which is used in the treatment of some leukemias (Figure 6.14 cf. Chapter 8). Nucleoside derivatives of fluorouracil (e.g., capecitabine) are prodrugs that allow the oral administration of 5-FU in cancer chemotherapy. The mechanism of action of these nucleosides is detailed in Chapters 7 and 8. Nucleosides having a trifluoromethylated base have been described for example, trifluridine is active on herpesvirus (Figure 6.14). 

An amino or hydroxy group facilitates 5-bromination even in aqueous solution. A -bromosuccinimide (NBS) and molecular bromine are the commonest reagents used. In uracils, cytosines, and barbituric acids, products of both addition and substitution can be identified in aqueous solution, and 5,5-dibromo products are common. In the bromination of uracils, addition products, including covalent hydrates, form rapidly, and the acid-catalyzed dehydration step to 5-bromouracils is much slower. Cytosine and related compounds behave similarly <1994HC(52)1, 1996CHEC-II(6)93>. 

There is evidence32,45 that two photo-reactivated products are formed in uracil photolysis one of these is the known dimer. The relative amounts of these two products are a function of initial uracil concentration and the time between irradiation and examination, since the... 

Pyrimidine is a weaker base than pyridine because of the presence of the second nitrogen. Its conjugate acid is a much stronger acid (pATa = 1.0). The pA a values of the N-l hydrogen in uracil, thymine and cytosine are 9.5, 9.8 and 12.1, respectively. Pyrimidine is a hygroscopic solid (b.p. 123-124 °C, m.p. 20-22 °C) and soluble in water. 

Cytosine and thymine were first isolated by hydrolysis of calf thymus tissue by Albrecht Kossel (1853-1927) and A. Neumann during 1893-1894. Thymine s structure was published in 1900 and confirmed over the next several years when it was synthesized by several investigators. In 1903, cytosine was synthesized by Henry Lord Wheeler (1867-1914) and Treat B. Johnson, confirming its structure. Uracil was first isolated in 1900 from yeast nucleic acid found in bovine thymus and herring sperm. The methylation of uracil produces thymine thymine is also called 5-methyluracil because methylation takes place at the fifth carbon in uracil to produce thymine. 

The 5,6-double bond in uracil, 5-fluorouracil, /V-alkyluracils, thiouracils, and uridines adds sodium sulfite or bisulfite to give the corresponding 5,6-dihydro-6-sulfonic acid salts. Bisulfite addition to cytosines and cytidine may be succeeded by a second reaction involving nucleophilic replacement of the amino group, for example, by water. 

As in the case of cytosine, several NMR and NQR studies were performed in search of the predominating tautomeric structures of uracil and thymine and their nucleotides and nucleosides. Investigation of PMR spectra of these compounds in nonaqueous solvents, such as dimethyl sulfoxide, localized the mobile protons in a number of 5- and 6-substituted uracils.59,61,328 These and similar studies63,85,329,330 indicated that dilactam structure 32 predominates in uracil compounds in aqueous and nonaqueous solutions as well as in the solid state. Proton and N-15 magnetic resonance spectra of several pyrimidines85 confirmed the diketo structure usually ascribed to uracil. 

As far as we are aware, there is no other quantitative evaluation of the influence of substituents on.the tautomeric equilibria in uracil except that due to Katritzky and Waring.97... 

Distribution of ir-Electron, o-Electron and Total Electron Density The 7r-charge and u-charge densities as well as total electron densities in uracils and thymines have been calculated abundantly. The charge distributions or gross atomic populations for uracils and thymines calculated by different methods can be found in the following papers ... 

Fig. 10. Net w-charges in uracil calculated by different methods (from top to bottom 77-HMO, w-SCF MO, EHT, IEHT, CNDO/2). Data taken from Pullman and Pullman.1 222,223,220...

OCH3, SH, NH2, CHg, or COOH,205 adenine-thymine base pair171,175,184, 185 and its cationic and anionic forms209 (for the charge densities at C-5 and C-6 positions in uracil, thymine, 5-amino- 5-nitro- and 6-methyl-uracil, 6-azathymine and orotic acid, see refs. 187, 188) it-HMO + a-Del Re calculations on uracil,369,397 5-fluoro- and 5-bromouracil,397 5,6-dihydrouracil and its anionic form369 n-SCF MO + a-Del Re... 

In Figs. 10-13 we have presented 7r-charges and total densities in uracil and thymine as calculated by different methods. The calculations... 

Fig. 12. Total net charges in uracil calculated by different methods (from top to bottom w-HMO + a-Del Re, w-SCF MO + a-Del Re, EHT, IEHT, CNDO/2, nonempirical). Data taken from Pullman and Pullman1 222-223 228 and from Stewart229 (nonempirical). Experimental229 net gross valence atomic populations for uracil are underlined [two sets of experimental numbers were obtained by the use of the L-shell standard STO s and L-shell SCF AO s scattering factors (in brackets), respectively]. The estimated standard deviations referring to the last decimal place are given in parentheses.

Energies of the Lowest Empty (LEMO) and Three Highest Occupied (HOMO) Molecular Orbitals in Uracil and Thymine0 Calculated by All-Valence and All-Electron Methods... 

Miles et a/.418 to be of the n — it type and correlated with the B2u, Blu, and Elu bands of benzene. The absorption at 180 nm in uracil, according to Miles et aZ.,418,421 covers a fifth it -> n transition. A recent study405 of the influence of an electric field on the light absorption of uracil and thymine in solution confirms that in the region < 255 nm the long-wavelength band of uracil overlaps a second transition which is hidden in the absorption spectrum. Similarly, in thymine the second transition appears below 275 nm. In both cases, however, no conclusion as to the nature of the weak bands was given. 

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