Diketo Form Research Articles

Reaction Mechanism of Uracil Bromination by HBrO: A New Way To Generate the Enol−Keto Form of 5-Bromouracil

Knowledge on the uracil bromination reaction is helpful for understanding the origin of the mutagenicity of 5-bromouracil (BrU). To get more details about this reaction, we explore the corresponding reaction mechanism by theoretical method. A total of seven pathways were studied for this purpose. The diketo form of BrU is observed as the main product in these pathways, which agrees well with experimental results. The most energy-favorable reaction pathway is found to be that Br and OH attacked the opposite sides of uracil. The reaction intermediate reported in the experiment is predicted to be reasonably stable. In the following step, a dehydration process occurs between H11 and O13-H14 when there are no explicit H(2)O taking part. However, when there are explicit water molecules in the environment, explicit H(2)O will lower the reaction barrier in the formation of reaction intermediates and the final product BrU. A proton-transfer process from C5 to O10 is facilitated by explicit H(2)O, which results in enol-keto form intermediate of this modified base (defined as BrU*). These results indicate a new way to generate the enol-keto form of BrU.

Tautomeric and Conformational Properties of Acetoacetamide: Electron Diffraction and Quantum Chemical Study

The tautomeric properties of acetoacetamide, CH3C(O)CH2C(O)NH2, have been investigated by gas electron diffraction (GED) and quantum chemical calculations (B3LYP and MP2 approximations with 6-31G(d,p) and 6-311++G(3df,pd) basis sets). GED results in a mixture of 63(7)% enol tautomer and 37(7)% diketo form at 74(5) degrees C. Only one enol form with the O-H bond adjacent to the methyl group (CH3C(OH)=CHC(O)NH2) and only one diketo conformer (with dihedral angles tau(O=C(CH3)-C-C) = 31.7(7.5) degrees and tau(O=C(NH2)-C(H2)-C(O)) = 130.9(4.5) degrees ) are present. The calculated tautomeric composition varies in a wide range depending on the quantum chemical method and basis set. Only the B3LYP method with small basis sets reproduces the experimental composition correctly.

DFT Study of Water-Assisted Intramolecular Proton Transfer in the Tautomers of Thymine Radical Cation

Density functional theory calculations are applied to investigate the intramolecular proton transfer in the tautomers of thymine radical cation and its hydrated complexes with one water molecule. The optimized structures and energies for 6 tautomers and 6 transition states of thymine radical cation are calculated at the B3LYP/6-311++G(d,p) level. It is predicted that the order of relative stability for the keto and enol tautomers of thymine radical cation is the same with that of the neutral thymine tautomers, though the enol tautomers are more stabilized with respect to the di-keto form in the radical cation than in the neutral state. A new channel of proton transfer from >C5-<TEX>$CH_{3}$</TEX> of thymine is found to open and have the lowest energy barrier of other proton transfer processes in thymine radical cation. The roles of hydration are also investigated with thymine-water 1 : 1 complex ions. The presence of water significantly lowers the barrier of the proton transfer, which clearly shows the assisting role of hydration even with one water molecule

Modeling of Hydrogen Bonds in Monohydrated 2,4-Dithiothymine: An Ab Initio and AIM Study

Twelve tautomers of 2,4-dithiothymine are calculated at the MP2/6-31+G(d) level, and the most stable one is referred to the di-keto form (P12). Then four H-bonded complexes between P12 and water are optimized at the MP2/6-31+G(d) level of theory. The calculation of vibrational frequencies and natural bond orbital analysis are also carried out at the same level to investigate the hydrogen bonds involved in all the systems. Within all the four complexes, three types of hydrogen bonds are formed, in which the O-H...S and N-H...O bonds are the normal bonds with the X-H bond elongation and red shift of the corresponding stretch frequencies, while the C-H...O interaction is an improper, blue-shifting hydrogen bond accompanied with the contraction of the C-H bond and a blue shift of the C-H stretch frequency. The topological properties are investigated with the atoms-in-molecules (AIM) theory. The NMR chemical shielding for the isolated and the four monohydrated 2,4-dithiothymine are calculated using the "gauge-including atomic orbital" (GIAO) method. The 1H chemical shifts are influenced by the formation of hydrogen bonds.

Resonance electron capture by uracil derivatives

The enol forms of uracil and its derivatives were detected in the gas phase by mass spectrometry. The [M - H]− ion is produced by resonance electron capture to the lowest unoccupied molecular orbitals, the process being accompanied by the detachment of the hydrogen atom from the nitrogen atom of the diketo form (low-energy peak at 0.8 eV) and from the oxygen atom of the enol form (in the energy region of 1.4 eV). The gas phase contains ∼10−3% of the enol form.

Diketoacid HIV-1 Integrase Inhibitors: An Ab Initio Study

The stable tautomeric forms of two representative arene-substituted diketoacid HIV-1 integrase inhibitors, 5-ClTEP and L-731,988, were investigated by B3LYP with 6-31G*, 6-31G(d,p), and 6-31+G(d,p) basis sets. Optimization with MP2/6-31G* was also performed for 5-ClTEP. The solvation effect was considered using a conductor-like screening model. With the density functional theory method, the trans diketo conformations are more stable than the cis conformers. The difference is 14 kJ mol(-1) for 5-ClTEP and 33 kJ mol(-1) for L-731,988. Two trans diketo structures were obtained. The difference between these two trans diketo structures is less than 4 kJ mol(-1) calculated at the B3LYP/6-311+G(3df,2p) level. Two enol forms prevail over the diketo tautomers and are calculated to have the same free energy. Because there is no barrier observed between these two enol forms, they can interchange easily such that a delocalized transition state is suggested to be the observed form. Contradictory to the results of the MP2 method that predicts a preference for the trans diketo forms, the B3LYP method predicts a preference for the enol tautomers, which is in agreement with the experimental results.

Gas phase ionization of 1,3-propanedial tautomeric forms: A theoretical study

Two stable 1,3-propanedial tautomers and three their anions have been studied theoretically at MP2 and DFT levels of theory. The energies, structural parameters, ionization potentials, and vibration frequencies have been calculated at the two theoretical levels in order to compare the accuracy of the methods used. The ionization potential of the end form of 1,3-propanedial enol form was estimated to be 752 kJ mol−1; the first and second potentials of the diketo form of 1,3-propanedial are 661 and 1239 kJ mol−1, respectively.

Systematic Study of the Tautomerism of Uracil Induced by Proton Transfer. Exploration of Water Stabilization and Mutagenicity

To systematically investigate all the possible tautomerisms from uracil (U) and its enol form (U) induced by proton transfer, we describe a study of structural tautomer interconversion in the gas phase, in a continuum solvent, and in a microhydrated environment with 1 or 2 explicit water molecules, using density functional theory (DFT) calculations by means of the B3LYP exchange and correlation functions. A total of 62 geometries including 25 transition states were optimized, and the geometrical parameters have been discussed. Some rules of the configuration variation in tautomerization were summarized. The relative stabilities of all the tautomers were established. When a proton transfers from the di-keto form to the keto-enol form, water molecules in different regions show absolutely opposite effects: some assist, whereas others hinder the tautomerization. However, when a proton transfers from the keto-enol form to the di-enol form, water molecules in different regions show similar effects: the Gibbs free energy always increases and the activation energy always decreases. Additionally, some important factors that obviously affect the activation energy and Gibbs free energy were found and discussed in detail. The reasons that water molecules can assist or prevent the proton transfer were given. Furthermore, on the basis of our calculated results, we explain why it is hard to detect the di-enol form of uracil in general experiments.

Solvent-controlled generation of two pairs of mononuclear single-strand helical copper(II) complexes of 2,6-pyridinediylbis(2-pyridinyl)methanone: metal-promoted hydrolysis and solvolysis with asymmetric induction

Two pairs of stable mononuclear single-strand helical complexes were obtained through controlled self-assembly using 2,6-pyridinediylbis(2-pyridinyl)methanone (L) and copper(II) salts. CuL(NO 3) 2 ( 1) and [CuL′(H 2O)](NO 3) 2 ( 2) represent a pair in which L takes the diketo form in 1 but hydrolyzed in 2, while CuLCl 2 ( 3) and [CuL″Cl]Cl ( 4) constitute another pair in which L remains intact in 3 but solvolyzed in 4. A mechanism of the metal-promoted hydrolysis and solvolysis of ligand L with asymmetric induction is proposed through studies on the crystal structures of these complexes.

DFT and experimental studies of the structure and vibrational spectra of curcumin

AbstractThe potential energy surface of curcumin [1,7‐bis(4‐hydroxy‐3‐methoxyphenyl)‐1,6‐heptadiene‐3,5‐dione] was explored with the DFT correlation functional B3LYP method using 6‐311G* basis. The single‐point calculations were performed at levels up to B3LYP/6‐311++G**//B3LYP/6‐311G*. All isomers were located and relative energies determined. According to the calculation the planar enol form is more stable than the nonplanar diketo form. The results of the optimized molecular structure are presented and compared with the experimental X‐ray diffraction. In addition, harmonic vibrational frequencies of the molecule were evaluated theoretically using B3LYP density functional methods. The computed vibrational frequencies were used to determine the types of molecular motions associated with each of the experimental bands observed. Our vibrational data show that in both the solid state and in all studied solutions curcumin exists in the enol form. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005

Theoretical study on the antioxidant activity of curcumin

AbstractThe computational results for curcumin at the B3LYP/6‐31G(d,p) level show that the enol form of curcumin is more stable than the diketo form because of an intramolecular hydrogen bond, which extends the conjugation effect in the enol chain, formed in the enol structure. Cis‐diketone form can not be obtained, presumably due to the strong repulsion between the carbonyl dipoles aligned h parallel. According to the phenolic OH bond dissociation enthalpy, curcumin in its most stable form can be suggested to be a relatively good antioxidant. In order to avoid overcoming H‐bond interaction and to improve the antioxidant activity of curcumin, a catechol moiety was incorporated into curcumin for designing a novel antioxidant. It is found that the designed molecule is much more efficient to scavenge radical than curcumin, comparable to vitamin E. Moreover, the ionization potential of the designed molecule is similar to that of curcumin, indicating that the designed molecule can not display the prooxidant effect.

Tautomeric and Conformational Properties of Methyl Acetoacetate, CH3OC(O)−CH2−C(O)CH3: Electron Diffraction and Quantum Chemical Study

The tautomeric properties of methyl acetoacetate, CH3OC(O)−CH2−C(O)CH3, have been investigated in the gas phase by gas electron diffraction (GED), IR(matrix) spectroscopy, and quantum chemical calculations (the MP2 approximation with 6-31G** and 6-311G(2df) basis sets and the B3LYP method with 6-31G** and 6-31++G** basis sets). GED results in a mixture of 80(7)% enol tautomer and 20(7)% diketo form at 309(6) K. Only one enol form with the O−H bond adjacent to the methyl group, CH3OC(O)−CHC(OH)CH3, is present. The GED analysis cannot distinguish between the three diketo conformers which are predicted by quantum chemical calculations. IR(matrix) spectra confirm the presence of a mixture of enol and keto forms with the enol tautomer strongly prevailing. Quantum chemical calculations with the MP2 approximation predict a very small contribution of the enol tautomer, in contrast to the experiments. B3LYP calculations, however, reproduce the experimental tautomeric mixture very closely.

Toward a reliable computational support to the spectroscopic characterization of excited state intramolecular proton transfer: [2,2 ′-bipyridine]-3,3 ′-diol as a test case

Time-dependent density functional theory is applied to calculate vertical absorption and emission energies of different tautomers of [2,2 ′-bipyridine]-3,3 ′-diol both in vacuo and in solution. The relative stabilities of diketo and dienol tautomers predicted at MP2 and B3LYP levels are close and significantly different from the HF results. Solvent effects further stabilize the diketo form, which, in aqueous solution becomes just 3 kcal/mol less stable than its dienol counterpart. Time-dependent density functional theory absorption energies are in good agreement with experimental data, but different levels of geometry optimizations lead to significant differences. Also the Stokes shift of the fluorescence spectrum is correctly reproduced. These results show the potentialities of the combined density functional theory/polarizable continuum model approach for the study of structural, thermodynamic, and spectroscopic properties of large molecules in solution.

An ab initio/hybrid (ONIOM) investigation of biliverdin isomers and metal–biliverdin analogue complexes

Ab initio HF and DFT (BLYP, B3LYP) methods have been applied to the computation of three isomeric forms, diketo, keto–enol and dienol of biliverdin. The fully optimized structures so obtained are compared and the most stable isomer (diketo form) agrees well with the structure determined from X-ray crystallographic studies. Results of the calculations based on three methods, HF, BLYP and B3LYP have been compared with the experimental parameters. B3LYP method results are determined to be closest to the experimental results. Octaethyl dimethyl amido biliverdin as a free ligand while complexed with zinc(II) which forms a metal–biliverdin analogue complex Zn II(OEBNMe 2) has been fully optimized using PM3 and B3LYP methods. Comparison of calculated parameters for this complex with X-ray results has proved the capability of the ab initio method in accurately predicting fine details of the complex. Results obtained by employing a hybrid (ONIOM) calculation method on such system for the first time has established the applicability as well as low computational cost of the technique.

Electronic excitation and singlet-triplet coupling in uracil tautomers and uracil-water complexes

Electronic spectra of uracil in its diketo (lactam) form and five enol (lactim) tautomeric forms have been investigated by means of combined density functional and configuration interaction methods. We have simulated the effects of hydrogen bonding with a protic solvent by recomputing the spectrum of uracil in the presence of two, four, or six water molecules. Geometries of the electronic ground state and several low-lying excited states have been optimized. Spin-orbit coupling has been determined for correlated wavefunctions employing a non-empirical spin-orbit mean-field approach. In accord with experiment, we find the diketo tautomer to be the most stable one. The calculations confirm that the first absorption band arises from the 1( π↦π*) S0↦S2 excitation. The experimentally observed vibrational structure in this band originates from a breathing mode of the six ring. Complexation with water molecules is seen to cause a significant blue shift of n↦π* excitations while leaving π↦π* excitations nearly uninfluenced. Computed radiative lifetimes are presented for the experimentally known weak phosphorescence from the π↦π* excited T1 state. Among the uracil lactim tautomers, one is particularly interesting from a spectroscopic point of view. In this tautomer, the π↦π* excitation gives rise to the S1 state.

Keto–enol tautomerism in β‐ketoesters: CH3C(O)CHXC(O)OY (X = H, Cl; Y = CH3, C2H5). Vibrational analyses, NMR spectra and quantum chemical calculations

AbstractThe tautomeric equilibria of the β‐ketoesters [CH3C(O)CH2C(O)OCH3 (I), CH3C(O)CHClC(O)OCH3 (II), CH3C(O)CH2C(O)OCH2CH3 (III) and CH3C(O)CHClC(O)OCH2CH3 (IV)] were studied by NMR spectroscopy and, in the case of I and II, by quantum chemical calculations (ab initio and density functional methods). In addition, liquid‐state Fourier transform infrared and Raman spectra were analysed for all four compounds. They revealed the existence of two tautomers, diketo and enol forms. In the NMR spectra only signals for the diketo form could be observed for I and III. However, the calculations for I and II predicted the enol structures to be the most stable species. Copyright © 2001 John Wiley &amp; Sons, Ltd.

A laser flash photolysis study of curcumin in dioxane-water mixtures.

Curcumin [bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] was studied by means of UV-VIS absorption spectroscopy and nanosecond laser flash photolysis in 1,4-dioxane-water mixtures in a series of dioxane-water volume ratios. The transient characteristics were found to be dependent on the amount of water. In pure dioxane the triplet state of the molecule in its enolic form was detected (lambda(max) = 720 nm, tau = 3.2 micros), whereas upon water addition, the diketo form was found to prevail, because of the perturbation of intramolecular H-bonded structure. This led to hydrogen abstraction from dioxane by curcumin triplet state and the formation of the corresponding ketyl radical (lambda(max) = 490 nm, tau approximately 10 micros). Laser flash photolysis measurements, carried out in solvents of different polarity and proticity (benzene, cyclohexane and various alcohols), allowed the transient assignments to be confirmed, supporting our interpretation.

The chemical structure of mumbaistatin, a novel glucose-6-phosphate translocase inhibitor produced by Streptomyces sp. DSM 11641.

The characterization of the structure of mumbaistatin (1), an effective inhibitor of the glucose-6-phosphatase system (EC 3.1.3.9), is reported. Isolation of mumbaistatin from cultures of Streptomyces sp. DSM 11641 was achieved by anion-exchange and reversed-phase chromatography. The acid-labile inhibitor was methylated for the structure determination. Single-crystal X-ray structure analysis of a triply methylated dehydration product, C31H24O11, revealed the structure of an aromatic dispirodiketal (2), a compound containing a previously undescribed ring system. Extensive 2D-NMR experiments with mumbaistatin and with the methylation products showed that mumbaistatin itself possesses the hydroxydiketodicarboxylic acid structure 1, C28H20O12, which, in the presence of acid or upon activation through methyl ester formation, undergoes self-condensation with loss of water to the dispirodiketal form (2). Mumbaistatin is an anthraquinone derivative, whose open-chain diketo form acts as a specific and powerful inhibitor of glucose-6-phosphate translocase: IC50=5 nM. The activity towards the same enzyme of the cyclized dispirodiketal derivatives is roughly one thousand times lower.

Effect of solvent on the excited-state photophysical properties of curcumin.

Photophysical properties of curcumin, 1,7-bis-(4-hydroxy-3-methoxy phenyl)-1,6-heptadiene-2,5-dione, a pigment found in the rhizomes of Curcuma longa (turmeric) have been studied in different kinds of organic solvent and also in Triton X-100 aqueous micellar media using time-resolved fluorescence and transient absorption techniques having pico and nanosecond time resolution, in addition to steady-state absorption and fluorescence spectroscopic techniques. Steady-state absorption and fluorescence characteristics of curcumin have been found to be sensitive to the solvent characteristics. Large change (delta mu = 6.1 Debye) in dipole moments due to photoexcitation to the excited singlet state (S1) indicates strong intramolecular charge transfer character of the latter. Curcumin is a weakly fluorescent molecule and the fluorescence decay properties in most of the solvents could be fitted well to a double-exponential decay function. The shorter component having lifetime in the range 50-350 ps and percent contribution of amplitude more than 90% in different solvents may be assigned to the enol form, whereas the longer component, having lifetime in the range 500-1180 ps with less than 10% contribution may be assigned to the di-keto form of curcumin. Our nuclear magnetic resonance study in CDCl3 and dimethyl sulfoxide-D6 also supports the fact that the enol form is present in the solution by more than about 95% in these solvents. Excited singlet (S1) and triplet (T1) absorption spectrum and decay kinetics have been characterized by pico and nanosecond laser flash photolysis. Quantum yield of the triplet is low (phi T < or = 0.12). Both the fluorescence and triplet quantum yields being low (phi f + phi T < 0.18), the photophysics of curcumin is dominated by the energy relaxation mechanism via the internal conversion process.

Structure and tautomeric properties of thymine derivatives generated by hydroxyl radical in anaerobic conditions

The tautomeric properties of three hydroxyl radical thymine derivatives were characterised by gradient geometry optimisation in the 6311G** basis set and MP2 (6311G**) energy calculations. The solvent effects were also estimated based on SCIPCM (6311G**) model. Calculations were applied to following main products of thymine degradation of hydroxyl radical in anaerobic conditions: 5-hydroxy-6-hydrothymine ( 1), 6-hydroxy-5-hydrothymine ( 2) and 5,6-dihydrothymine ( 3). The most stable tautomer of 5-hydroxy-6-hydrothymine ( 1) is in diketo form with 5eq conformation of the chiral C 5 carbon atom. Among all studied tautomers of 6-hydroxy-5-hydrothymine ( 2) the 15eq6ax tautomer (diketo isomer with C 5 equatorial and C 6 axial orientations) is the preferred one. The most probable 5,6-dihydrothymine ( 3) tautomer is in diketo form with equatorial orientation of the C 5 chiral centre. No significant impact of the solvent polarity on the order of tautomers was observed. Since in all cases the most stable tautomeric form corresponds to diketo isomer, the coding abilities are the same and may be described as (donors on O 2 and O 4 oxygen atoms and acceptor on H 3 hydrogen atom).