Uracil deprotonation

Itaya s group presented images of benzene, naphthalene and anthracene on Cudll), and naphthalene and anthracene on Rh(l 11)/ Wandlowski and coworkers monitored adsorption of uracil on gold surfaces They reported imaging chemisorbed molecules as well as physisorbed molecules and determined their adlattice structures. They also made a correlation between the structure and lateral interaction forces of adsorbed molecules. They showed that application of sufficiently positive electrode potentials results in uracil deprotonation, leading to different surface structure and geometric orientation. 

An interesting dinically useful prodrug is 5-fluorouracil, which is converted in vivo to 5-fluoro-2 -deoxyuridine 5 -monophosphate, a potent irreversible inactivator of thymidylate synthase It is sometimes charaderized as a dead end inactivator rather than a suicide substrate since no electrophile is unmasked during attempted catalytic turnover. Rathei since a fluorine atom replaces the proton found on the normal substrate enzyme-catalyzed deprotonation at the 5 -position of uracil cannot occur. The enzyme-inactivator covalent addud (analogous to the normal enzyme-substrate covalent intermediate) therefore cannot break down and has reached a dead end (R. R. Rando, Mechanism-Based Enzyme Inadivators , Pharm. Rev. 1984,36,111-142). 

Deprotonation provides the necessary electron push to kick out the electron pair joining C(6) with the nitrobenzene oxygen. If, however, N(l) is alkylated (as with the nucleosides and nucleotides), OH catalysis is much less efficient since it now proceeds by deprotonation from N(3) (with the uracils) or from the amino group at C(4) (with the cytosines). In these cases the area of deprotonation is separated from the reaction site by a (hydroxy)methylene group which means that the increase in electron density that results from deprotonation at N(3) is transferable to the reaction site only through the carbon skeleton (inductive effect), which is of course inefficient as compared to the electron-pair donation from N(l) (mesomeric effect) [26]. Reaction 15 is a 1 1 model for the catalytic effect of OH on the heterolysis of peroxyl radicals from pyrimidine-6-yl radicals (see Sect. 2.4). 

A number of papers have reported studies on pyrimidine radical cations. 1-Methylthymine radical cations generated via a triplet-sensitized electron transfer to anthraquinone-2,6-disulfonic acid were detected by Fourier transform electron paramagnetic resonance (FTEPR). The parent 1-methylthymine radical cation, and its transformation to the N(3)-deprotonated radical cation, were observed. Radical cations formed by addition of HO and POs" at C(6) were also detected depending on the pH. Similarly, pyrimidine radical cations deprotonated at N(l) and C(5)-OH were detected from the reaction of 804 with various methylated pyrimidines." These radicals are derived from the initial SO4 adducts of the pyrimidines. Radical cations of methylated uracils and thymines, generated by electron transfer to parent ions of... 

To bracket the N3 site, we must perform the deprotonation of uracil under conditions that will allow the N3" to be sustained that is, we remove the NU/N3" mixture from the... 

In addition to N-deprotonation, pyrimidinones can also be G-metallated. Lithiation at the 6-position of uracils and related uridines and thymidines can be achieved with butyllithium or LDA provided that the hydroxyl groups of the sugar are protected in the case of the nucleoside derivatives <1993AHC(56)155, 2006JOC8842>. When the... 

These ideas have been illustrated in a recent study of the co-crystalline complex of 1-meCyt 5-FUra [19]. Using model calculations, it was shown how the hydrogen-bonding network of the crystal is able to sustain a proton shuttle which leads to the selective formation of certain radicals. Calculations predict that the site of reduction would be the cytosine base, yielding the N3 protonated cytosine anion, Cyt(N3-I-H), while the uracil base would be the site of oxidation, yielding the N1 deprotonated uracil cation, Ura(Nl—H) ... 

Both uracil and thymine deprotonate at N-l or N-3 325,326 (forms 34 and 35, respectively), as initially proposed by Nakanishi et al.32i on the basis of the UV study of anions of uracil and of its N-l- and N-3-methyl derivatives. 

Deprotonation of the secondary amino group of 2,5 -iminonucleosides 69 (X = NR1 R1 = Me, Ph, PhCH2 R= Me, Ph) (Scheme 11) created the nucleophilic center which attacked intramolecularly the aminal carbon atom of 69 producing the uracil derivatives 70 in moderate yields <1990J(P1)3027>. 

A comparison of aliphatic amides, cyclic amides, cyclic imides and 2,4-dioxopyrimidines (uracils) in their deprotonated and diplatinated form (Scheme 4) reveals an increasing steric shielding of the V-bonded Pt ion (Ptx). With respect to formation of stacked and partially oxidized dinuclear species, it is evident that application of the binding principles seen in the blues of cyclic amides to the uracils and imides allows for tetranuclear species only. On the other hand, the presence of an additional O-donor in the imides and uracils (and likewise the cytosines, vide infra) provides an... 

On the other hand, electrophilic metal binding at C(5) with consequent deprotonation of this site was observed [12], Mono- (at C(5)) [18-20] and di-deprotonated species (C(5),N(4)) [21] have been reported. The shorthand used to represent deprotonation at C(5) for uracils and cytosines bears the negative charge before the shown AT-bonded H-atoms. In the Table, the shorthand for these anions is reported in italics. 

The binding mode of uracils and thymines in neutral and deprotonated forms has been reviewed up to 1987 [13]. They coordinate hard, and relatively few soft metal ions, through 0(4) (preferentially) and 0(2). Uracil (thymine) behaves as a weak dibasic acid in alkaline media with the more basic site N(3) at pKa 9.69 (10.16), as compared to N(l) at pKa 14.2. At high pH the monoanions of uracil and thymine bind the metal ions preferentially via N(l). However, the N(3) linkage isomer of the Ptn complex has also been obtained [24]. The relatively few examples of complexes with soft metal ions, containing monodentate uracilate anions, are due to the high tendency of the ligand to bind additional metal ions to form polynuclear species [13]. 

The uracilate and thyminate anions simultaneously bind the metals through N(3) and 0(4), whereas the 1-methylcytosinate anions do so through N(3) and the deprotonated amino group N(4) [14]. The neutral cytosine was found also to act as bridging ligand through N(3) and 0(2) [33]. 

In aqueous sulfuric acid 3,5-dihydroxy-l,2,4-triazine is brominated 10 ° times more slowly than uracil, but with some mechanistic similarities. Provided that there is at least one NH group present, bromine can react with the deprotonated anionic species analogous to 10.24 (76JOC4004). 

Computed properties of orotate derivatives other than the energetics of decarboxylation have also been published. The computed gas phase proton affinities of the 2- and 4-oxygens of orotate and of C6-deprotonated uracil have been reported by Lee and Houk to be 263 and 274 kcal mol-1, respectively, for orotate 02 and 04, and 285 and 302 kcal mol-1 for deprotonated uracil 02 and 04.16 The authors noted that the greater proton affinity of the 4-oxygen is relevant to the favorability of the 4-protonation pathway. Similar observations were made by Singleton, Beak and Lee and Phillips and Lee.46,47 Kollman and coworkers recently found that the most basic site of orotate appears to be C5, which is calculated to be 7 kcal mol-1 more basic than 04 at MP2/6-31 + G7/HF/6-31 + G. 27 This translates to a very low energy barrier for decarboxylation of the C5 protonated intermediate 10 kcal mol-1 at MP2/6-31 +G7/HF/6-31 + G, and 5 kcal mol-1 at MP2/cc-pVDZ. SCRF sol-... 

The proton affinity and acidity of uracil itself (2a) has also been the subject of computational investigation, primarily by the groups of Zeegers-Huyskens and Lee.52-57 Lee and coworkers have also conducted a series of experimental investigations that have established that uracil has four sites that are more acidic than water (Nl, N3, C5, and C6) and that 04 is 8 kcal mol-1 more basic than 0254-56 Gronert and coworkers also conducted clever mass spectrometric experiments that effected decarboxylation of orotate to form the C6-deprotonated uracil (3a), which was then used to measure the acidity of the C6-H.57,58a Gronert s calculations and experiments, later confirmed by Lee and Kurinovich using different uracil derivatives,55 established that the C6 site of uracil is quite acidic with a gas phase acidity (A//acid) of —369 kcal mol-1, this site is as acidic as acetone. Recent experiments in water, however, indicate that the C6-H of 1,3-dimethyl uracil has a pK of 34, considerably less acidic than that of acetone (pA a — 19).58b... 

The relationships between the deprotonation energy of proton donor and complex stability as well as its VDE were characterized in our work devoted to complexes between uracil and a series of alcohols with deprotonation enthalpy (HDP) varied in a systematic manner [48], We found out that a H p smaller than 14.3 eV is required for BFPT with the product being UH OR. Two minima coexist on the anionic energy surface for 14.8 eV < HDP < 14.3 eV. These minima correspond to the UH OR and 1 HOR structures. For ROH s with deprotonation enthalpies above 14.8 eV only the U HOR minimum exists on the potential energy surface. 

In Figure 21-17 the dependence of the stabilization energy in anionic uracil-alcohol complexes vs. the deprotonation energy (EDP) of alcohol (ROH) is shown [48], On the other hand, Figure 21-18 depicts the variation in VDE with the EDP of ROH [48],... 

The energy of stabilization of the anionic complex increases when acidity of alcohols increases (Figure 21-17). For anionic complexes for which we identified two minima corresponding to U HOR and UH OR structures, the structure with protonated uracil is more stable. The vertical detachment energy of anionic complex systematically increases when deprotonation energy of alcohol decreases. There is a discontinuity in VDE of ca. 0.5 eV, which is a manifestation of intermolecular proton transfer (Figure 21-18). 

Figure 21-17. The stabilization energy (E b) in anionic uracil-alcohol complexes vs the deprotonation energy (EDP) of ROH. All properties calculated at the B3LYP/6-31+-t-G (5d) level of theory (Figure 6 of ref. [48], Reprinted with permission. Copyright 2005 American Chemical Society.)...

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