COSMO Solvation Model Research Articles

Conformational studies on the prion protein 115–122 fragment

The conformational properties of the 115–122 region of the prion protein (PrP) were investigated by means of molecular mechanics and DFT computations. From the results of the Monte Carlo Multiple Minimum conformational searches several representative groups could be distinguished. Analysis of these and other characteristic structures like the α-helix and the geometry of the 115–122 region of dissolved PrP (native) revealed the primary importance of N–H⋯O hydrogen bonding interactions in their stabilization, whereas the N–H⋯N interactions play only a marginal role. According to our PBE/TZVPP//RI-PBE/SVP DFT calculations, the isolated β-sheet and α-helical regular secondary structures and the native geometry are less stable than γ-turn, which proved to be the global minimum geometry of the isolated 115–122 PrP fragment. The different solvation energies in aqueous solution, however, change the above picture. The β-sheet structure can be considerable stabilized in water, becoming the most favoured at the PBE/TZVPP//RI-PBE/SVP level using the COSMO solvation model. These results support a possible formation of the β-sheet structure of small PrP fragments involving the 115–122 region in aqueous solution, and in this way the proposed mechanism of their inhibition of the PrP(endogenous) → PrP(pathogenic) conversion.

Why Are Ionic Liquids Liquid? A Simple Explanation Based on Lattice and Solvation Energies

We have developed a simple and quantitative explanation for the relatively low melting temperatures of ionic liquids (ILs). The basic concept was to assess the Gibbs free energy of fusion (Delta(fus)G) for the process IL(s) --> IL(l), which relates to the melting point of the IL. This was done using a suitable Born-Fajans-Haber cycle that was closed by the lattice (i.e., IL(s) --> IL(g)) Gibbs energy and the solvation (i.e., IL(g) --> IL(l)) Gibbs energies of the constituent ions in the molten salt. As part of this project we synthesized and determined accurate melting points (by DSC) and dielectric constants (by dielectric spectroscopy) for 14 ionic liquids based on four common anions and nine common cations. Lattice free energies (Delta(latt)G) were estimated using a combination of Volume Based Thermodynamics (VBT) and quantum chemical calculations. Free energies of solvation (Delta(solv)G) of each ion in the bulk molten salt were calculated using the COSMO solvation model and the experimental dielectric constants. Under standard ambient conditions (298.15 K and 10(5) Pa) Delta(fus)G degrees was found to be negative for all the ILs studied, as expected for liquid samples. Thus, these ILs are liquid under standard ambient conditions because the liquid state is thermodynamically favorable, due to the large size and conformational flexibility of the ions involved, which leads to small lattice enthalpies and large entropy changes that favor melting. This model can be used to predict the melting temperatures and dielectric constants of ILs with good accuracy. A comparison of the predicted vs experimental melting points for nine of the ILs (excluding those where no melting transition was observed and two outliers that were not well described by the model) gave a standard error of the estimate (s(est)) of 8 degrees C. A similar comparison for dielectric constant predictions gave s(est) as 2.5 units. Thus, from very little experimental and computational data it is possible to predict fundamental properties such as melting points and dielectric constants of ionic liquids.

Computational Study of Aqueous Reactions in Tocopherol Regeneration.

The α-tocopheroxyl radical, resulting from the scavenging of the peroxyl radical by α-tocopherol (vitamin E) in the cell membrane, will further react with the peroxyl radical to form tocopherones. A computational study is presented of the aqueous proton-transfer reactions of the α-8a-(hydro-dioxy)tocopherone and α-8a-(methyl-dioxy)tocopherone to produce 1-benzopyrylium, the subsequent hydrolysis to 2H-1-benzopyran-6(8aH)-one, and the terminating rearrangement of 8a-hydroxytocopherone to 2,5-cyclohexadiene-1,4-dione. The alkyl tail of true tocopherol is replaced by methyl in these studies. Calculations of the structures and energies along the reaction pathways were first performed at the BP86/TZVP/DGA1 level with a COSMO solvent model, and additional solvent corrections from COSMO-RS theory were subsequently added. The proposed mechanism is found to be thermodynamically and kinetically feasible in water. The ion-mediated steps are found to have free-energies of activation under 3 kcal mol(-)(1), with kinetics likely to be diffusion-limited. The unimolecular rearrangement is the slow step, with a predicted reaction rate constant of 0.056 min(-)(1) at 298 K, in excellent agreement with the experimental value of 0.046 min(-)(1). Kinetic and thermodynamic properties of the ion-mediated steps are shown to rely strongly on the use of an accurate continuum solvation model. Distinct entropy and enthalpy contributions are determined from the temperature dependence of the predicted free energies.

Chemical Behavior of the Biradicaloid (HO···ONO) Singlet States of Peroxynitrous Acid. The Oxidation of Hydrocarbons, Sulfides, and Selenides

Various high levels of theory have been applied to the characterization of two higher lying biradicaloid metastable singlet states of peroxynitrous acid. A singlet minimum (cis-2) was located that had an elongated O-O distance (2.17 A) and was only 12.2 kcal/mol [UB3LYP/6-311+G(3df,2p)+ZPVE] higher in energy than its ground-state precursor. A trans-metastable singlet (trans-2) was 10.9 kcal/mol higher in energy than ground-state HO-ONO. CASSCF(12,10)/6-311+G(d,p) calculations predict the optimized geometries of these cis- and trans-metastable singlets to be close to those obtained with DFT. Optimization of cis- and trans-2 within the COSMO solvent model suggests that both exist as energy minima in polar media. Both cis- and trans-2 exist as hydrogen bonded complexes with several water molecules. These collective data suggest that solvated forms of cis-2.3H(2)O and trans-2.3H(2)O represent the elusive higher lying biradicaloid minima that were recently (J. Am. Chem. Soc. 2003, 125, 16204) advocated as the metastable forms of peroxynitrous acid (HOONO). The involvement of metastable trans-2 in the gas phase oxidation of methane and isobutane is firmly established to take place on the unrestricted [UB3LYP/6-311+G(d,p)] potential energy surface (PES) with classical activations barriers for the hydrogen abstraction step that are 15.7 and 5.9 kcal/mol lower than the corresponding activation energies for producing products methanol and tert-butyl alcohol formed on the restricted PES. The oxidation of dimethyl sulfide and dimethyl selenide, two-electron oxidations, proceeds by an S(N)2-like attack of the heteroatom lone pair on the O-O bond of ground-state peroxynitrous acid. No involvement of metastable forms of HO-ONO was discernible.

Electron Transfer within 2,7-Dinitronaphthalene Radical Anion

The optical spectrum of 2,7-dinitronaphthalene radical anion generated by Na(Hg) reduction in acetonitrile containing a large excess of cryptand[2.2.2] exhibits a Hush-type intervalence charge-transfer band at 1070 nm, estimated to correspond to an off-diagonal matrix coupling element of 310 cm(-)(1). The interpolated rate constant for intramolecular electron transfer at 293 K measured by ESR between 225 and 320 K for this solution is 3.1(+/-0.2) x 10(9) s(-)(1). Rate constants estimated in two ways from the optical parameters using the Marcus-Hush assumption that the diabatic surfaces should be parabolae are 1.0 and 0.11 x 10(9) s(-1), and those using diabatic surfaces that fit the observed charge-transfer band are 9.6 and 3.4 x 10(9) s(-)(1), when used with an electron-transfer distance on the adiabatic surfaces of 6.42 A. Similar measurements and comparisons were also carried out using dimethylformamide and butyronitrile as solvents. The success of simple, classical two-state Marcus-Hush theory precludes an electron-hopping mechanism. UHF calculations predict a planar unsymmetrical gas-phase structure for 1,3-dinitrobenzene radical anion but give serious spin contamination. Semiempirical AM1 calculations using singles excitation configuration interaction with an active space of 70 orbitals and the COSMO solvent model also give a planar unsymmetrical structure. These calculations make the internal vibrational component of the reorganization energy nearly constant, and much smaller than the solvent reorganizational component, and predict the transition energy to lie between that observed in acetonitrile (9360 cm(-1)) and those observed in dimethylformamide (8100 cm(-1)) and butyronitrile (8040 cm(-1)).

Relative stabilities of weakly coordinating anions: a computational study.

This article describes BP86/SV(P) (DFT) calculations on a representative set of weakly coordinating anions (WCAs) of type [M(L)n]-, their parent neutral Lewis acids M(L)(n-1) and their ate complexes with fluoride, that is, [FM(L)(n)](n-1) (M=B, L=F, OTeF5, C6H5, C6F5, C6H3(CF3)2, CF3; M=P, As, Sb, L=F, OTeF5; M=Al, L=OC(CF3)3). Compounds with fluoride bridges, that is, Sb(n)F(5n) and [Sb(n)F(5n+1)]- (n=2, 3, 4), Al2(L)5F and [(L)3Al-F-Al(L)3]- (L=OC(CF3)3), (F4C6[1,2-B(L)2]2, [F4C6[1,2-B(L)2]2F]-, [F4C6[1,2-B(L)2]2OMe]- (L=C6F5) were also calculated. Based on these BP86/SV(P) and auxiliary MP2/TZVPP, G2, and CBS-Q calculations the relative stabilities and coordinating abilities of these WCAs were established with regard to the fluoride ion affinities (FIA) of the parent Lewis acids, the ligand affinity (LA) of the WCAs, the decomposition of a given WCA in the presence of a hard (H+, proton decomposition PD) and a soft electrophile (Cu+, copper decomposition CuD), the position of the HOMO, the HOMO-LUMO gap, and population analyses of the anions providing partial charges for all atoms. To obtain data that is more reliable, the assessed quantities were calculated through isodesmic reactions. If parts of the calculations could not be done isodesmically, higher levels such as MP2/TZVPP, G2, and CBS-Q were used to obtain reliable values for these reactions. Although the obtained results can not be taken as absolute, the relative ordering of the stabilities of all WCAs will undoubtedly be correct, since a single methodology was chosen for the investigation. To include media effects the decomposition reactions of a subset of 14 WCAs with the SiMe3+ and [Cp2ZrMe]+ ions were also calculated in PhCl and 1,2-F2C6H4 (COSMO solvation model). We found that in most cases gas-phase calculations and solution calculations give comparable results for the stability of the anion. Applications of the LA and FIA that allow one to decide, on thermodynamic grounds, which WCA or Lewis acid is the most suitable for a given problem are sketched.

Prediction of Vapor Pressures and Enthalpies of Vaporization Using a COSMO Solvation Model

We have developed a general predictive method for vapor pressures and enthalpies of vaporization based on the calculation of the solvation free energy that consists of three components; the electrostatic, dispersion, and cavity formation contributions. The electrostatic contribution is determined using the quantum mechanical COSMO solvation model. Thermodynamic perturbation theory for hard-core molecules is used for the cavity term, and the dispersion term is modeled using a mean field term proportional to the density and molecular surface area. The proposed model uses one set of van der Waals atomic radii to describe molecular shape, two universal interaction parameters for the electrostatic interaction, one set of atom-specific dispersion coefficients, one universal parameter to scale the atomic exposed surface area, and a single universal parameter for the ratio of the hard-core to atomic radii. The model parameters have been determined using 371 pure substances of varying molecular structure, functionality, and size. The average accuracy of the model for vapor pressures and enthalpies of vaporization at the normal boiling temperature is found to be 76% and 4.81 kJ/mol, respectively, with temperature-independent parameters. The average error in the normal boiling temperature is found to be 16 K for species whose boiling points range from 191 to 610 K.

TD-DFT Computational Insight into the Origin of Wavelength-Dependent E/Z Photoisomerization of Urocanic Acid

DFT and TD-DFT calculations in the gas phase and water have been performed for both anionic and zwitterionic forms of urocanic acid (UA) to gain an insight into the origin of its wavelength-dependent E/Z photoisomerization. Theoretical examination of the rotational flexibility of the carboxylic acid group by the B3LYP/6-31+G(d,p) method in conjunction with the COSMO solvent model supports the earlier suggestion (Danielsson, J.; Soderhall, J. A.; Laaksonen, A. Mol. Phys. 2002, 100, 1873) that in aqueous solution the carboxylic acid group may rotate. Our TD-B3LYP results on vertical excitation energies for the different CCCOO- rotamers of zwitterionic UA indicate that deviation from planarity may lead to an alteration of the excited-state order. We suggest two possible singlet/triplet conical intersections (S2/T5 and S1/T3) located around 306 and 314 nm. A mechanistic discussion and simplified Jablonski-type diagrams are presented for three spectral regions where UA exhibits different photobehavior: (i) before S2/T5 (λ < 306 nm), (ii) between two, S2/T5 and S1/T3, intersections (306 nm < λ < 314 nm), and (iii) after S1/T3 (UV-A irradiation at λ > 314 nm). E/Z photoisomerization occurs in the narrow spectral region ii on the nπ* singlet excited surface. The comparison of molecular orbitals and an effective electronic potential analysis of anionic UA forms suggest that the excited state of parent N-anionic UA undergoes proton photoattachment, whereas T-anionic UA does not change its protonation state upon becoming excited. It is suggested that the formation of zwitterionic species from excited N-anionic UA is responsible for a similar photochemical behavior at different pH values (5.0 and 7.0) under the photostationary irradiation. The presence of the second tautomeric component can be one of the reasons for the slight differences for zwitterionic and anionic UA solutions observed experimentally in the transient absorption dynamics and fluorescence spectra.

A quantum mechanical study on phosphotyrosyl peptide binding to the SH2 domain of p56 lck tyrosine kinase with insights into the biochemistry of intracellular signal transduction events

A study on the interaction between a phosphotyrosyl peptide with the SH2 domain of Lck kinase has been undertaken with the aid of semiempirical linear-scaling quantum mechanical methods. The structure of this complex has been solved at atomic resolution and, hence, it represents the ideal candidate for studying the charge deformation effects induced by the phosphopeptide on the binding site. Substantial changes in the charge of amino acid residues located in the binding pocket of the protein are observed upon ligand binding. More specifically, our quantum chemical calculations indicate that H-bonds involving charged side-chains are subject to consistent charge deformation effects whereas those forming salt bridges are unaffected by ligand binding. Furthermore, ligand binding has the effect of changing both the magnitude and direction of the protein's macrodipole, which rotates approximately 150° with respect that of the unliganded protein. This suggests that a change in the polarization state of the protein might acts as a switch during the transmission of intracellular signals. The binding energy calculated with the aid of the COSMO solvation model corresponds to about −200 kcal/mol, most of which is attributed to the interaction of the phosphotyrosine head with the amino acid chains located in the binding site of the SH2 domain.

Theoretical analysis of peroxynitrous acid: characterization of its elusive biradicaloid (HO...ONO) singlet states.

Various high levels of theory (DFT, QCISD, BD(TQ), and CASSCF) have been applied to the characterization of two higher-lying biradicaloid singlet states of peroxynitrous acid. A singlet minimum (cis-2) was located that had an elongated O-O distance of 2.17 A and was only 14.4 kcal/mol [UB3LYP/6-311+G(3df,2p)] higher in energy than its cis-peroxynitrous acid ground-state precursor. A trans metastable higher-lying singlet (trans-2) was 12.8 kcal/mol higher in energy than ground-state HO-ONO. Complete active space calculations [CAS(12,10)/6-311+G(d,p)] predicted the optimized geometries of these cis and trans metastable singlets to be quite close to those obtained with the DFT method. Geometry optimization of both cis- and trans-2 within the COSMO solvent model suggest that both exist as energy minima in polar media with elongated O-O distances of 2.14 and 2.09 A. Both cis- and trans-2 exist as hydrogen-bonded complexes with several water molecules. These collective data suggest that solvated forms of cis-2.3H2O and trans-2.3H2O represent the elusive higher-lying biradicaloid minima that have been previously advocated (J. Am. Chem. Soc. 1996, 118, 3125) as the metastable forms of peroxynitrous acid (HOONO*).

A theoretical analysis of the conformational behaviour of substituted methylenecyclohexanes

The use of the PBE0 hybrid density functional theory method in conjunction with the COSMO solvation model allowed us to reproduce, both qualitatively and quantitatively, the experimentally observed conformational compositions of 2-substituted and 2,7-disubstituted methylenecyclohexanes. An analysis revealed several different interactions that influence the overall equilibrium. It was found that the endo (general) anomeric effect plays a significant role in the equilibrium and that the "unsaturation effect" possibly comprises two effects.Key words: conformational analysis, methylenecyclohexanes, anomeric effect, unsaturation effect.

DFT studies of uranyl acetate, carbonate, and malonate, complexes in solution.

The aim of this work is to demonstrate that theoretical chemistry can be used as a complementary tool in determining geometric parameters of a number of uranyl complexes in solution, which are not observable by experimental methods. In addition, we propose plausible structures with partial geometric data from experimental results. A gradient corrected DFT methodology with relativistic effects is used employing a COSMO solvation model. The theoretical calculations show good agreement with experimental X-ray and EXAFS data for the triacetato-dioxo-uranium(VI) and tricarbonato-dioxo-uranium(VI) complexes and are used to assign possible geometries for dicalcium-tricarbonato-dioxo-uranium(VI) and malonato-dioxo-uranium(VI) complexes. The results of this exercise indicate that carbonate bonding in these complexes is mainly bidentate and that hydroxo bridging plays a critical role in the stabilization of the polynuclear uranyl complexes.

New Density Functional and Atoms in Molecules Method of Computing Relative pKaValues in Solution

A theoretical structure−property relation between pKa and Bader's atoms in molecules (AIM) energy of the dissociating proton was obtained by an approximation of the standard gas-phase expression for the equilibrium constant expressed in terms of molecular partition functions. This relation was then tested by solvated density functional computations on a series of aliphatic carboxylic acids, substituted benzoic acids, phenols, anilinium ions, and pyridinium ions using the COSMO solvation model. Comparison with accurate experimental values indicates that average unsigned errors of generally less than 0.2 pKa units can be achieved in the calculation of relative pKa values. The inclusion of specifically hydrogen-bonded water molecules in the vicinity of the dissociating proton was found to improve the agreement between theory and experiment greatly. Computed pKa values for some diprotic acids were also investigated.

A theoretical study of tautomerism of 2,6-dithioxanthine in the gas and aqueous phases using AM1 and PM3 methods

Heats of formation, entropies, Gibbs free energies, relative tautomerisation energies, tautomeric equilibrium constants, dipole moments and ionisation potentials for the 14 possible tautomers of 2,6-dithioxanthine have been studied using semiempirical AM1 and PM3 quantum-chemical calculations at the SCF level, both in the gas and aqueous phases, with full geometry optimisation. The COSMO solvation model was employed for aqueous solution calculations. The calculations show that 2,6-dithioxanthine exists as the dithiol forms, but DTX (9,10,11) with N9H of imidazolic ring is more stable than the dithiol-N7H tautomer, DTX (7,10,11) in the gas phase. The predominant tautomer in the aqueous solution exists in an dithione form with the imidazole proton on N9, that is DTX(1,3,9). The results are in good agreement with UV experimental results. The entropy effect on the Gibbs free energy of the 2,6-dithioxanthine base is very small and practically has no significance for the tautomeric equilibria of the base. The enthalpic term is dominant in the determination of the equilibrium constant.

AM1 and PM3 study of tautomerism of xanthine in the gas and aqueous phases

Heats of formation, entropies, Gibbs free energies, relative tautomerisation energies, tautomeric equilibrium constants, relative proton affinities, dipole moments, and ionisation potentials for the fourteen possible tautomers of xanthine have been studied using semiempirical AM1 and PM3 quantum-chemical calculations at the SCF level in the gas and aqueous phases, with full geometry optimisation. The COSMO solvation model was employed for aqueous solution calculations. The calculations show that the two diketo tautomers X1,3,7 and X1,3,9 are the predominant species at room temperature in the gas and aqueous phase. But, the first more stable tautomer is the dioxo-7H tautomer, X1,3,7. Comparison with available experimental data provides support for quality of results derived from theoretical computations. The entropy effect on the Gibbs free energy of the xanthine is very small and there is little significance for the tautomeric equilibria of the base. The enthalpic term is dominant also in the determination of the equilibrium constant.

AM1 and PM3 studies of some thio analogues of pyrimidine bases in the gas and aqueous phases

AbstractHeats of formation, entropies, Gibbs free energies, relative tautomerization energies, dipole moments, and ionization potentials for the tautomers of 2‐thiocytosine, 2,4‐dithiouracil and 2,4‐dithiothymine and their 1‐methyl analogues were studied by using semiempirical AM1 and PM3 quantum‐chemical calculations at the SCF level both in the gas phase and in aqueous solution, with full geometry optimization. The COSMO solvation model was employed for aqueous solution calculations. The calculations show that the thiol‐amino tautomer of 2‐thiocytosine is the most stable in the gas phase whereas the thione‐amino tautomer is the most stable in the aqueous phase. For 2,4‐dithiouracil and 2,4‐dithiothymine, dithione tautomers are the most stable in both phases. The results are in good agreement with available experimental and theoretical results. The entropy effect on the Gibbs free energy of the thiopyrimidine bases is very small and has practically no significance for the tautomeric equilibria of thiopyrimidine bases. The enthalpic term is dominant in the determination of the equilibrium constant. Copyright © 2001 John Wiley &amp; Sons, Ltd.

Tautomerism of 6-thioguanine in the gas and aqueous phases using AM1 and PM3 methods

Heats of formation, entropies, Gibbs free energies, relative tautomerisation energies, tautomeric equilibrium constants, relative proton affinities, dipole moments and ionisation potentials for the fourteen possible tautomers of 6-thioguanine have been studied using semiempirical AM1 and PM3 quantum-chemical calculations at the SCF level, both in the gas and aqueous phases, with full geometry optimisation. The COSMO solvation model was employed for aqueous solution calculations. The calculations show that 6-thioguanine exists as the thiol-amino forms in the gas phase, whereas the thione-amino forms are the predominant tautomers in the aqueous solution. The N9(H) thiol is the most stable tautomer in the gas phase, while the thione-N1,7(H) tautomer is preferred in an aqueous solution. The results are in good agreement with available experimental and theoretical results. The entropy effect on the Gibbs free energy of the 6-thioguanine base is very small and there is little significance for the tautomeric equilibria of the base. The enthalpic term is dominant also in the determination of the equilibrium constant.

AM1 and PM3 Study of Tautomerism of Hypoxanthine in the Gas and Aqueous Phases

Heats of formation, entropies, Gibbs free energies, relative tautomerisation energies, tautomeric equilibrium constants, dipole moments, and ionization potentials for the eight possible tautomers of hypoxanthine have been studied using semiempirical AM1 and PM3 quantum-chemical calculations at the SCF level in the gas and aqueous phases, with full geometry optimization. The COSMO solvation model was employed for aqueous solution calculations. The calculations show that the two keto tautomers H17 and H19 are the predominant species at room temperature in the gas and aqueous phase. However, the tautomer H17 is the more dominant species in gas phase, while the H19 tautomer is the more dominant species in the aqueous phase. Comparison with available experimental data provides support for the results derived from theoretical computations. The entropy effect on the Gibbs free energy of hypoxanthine is very small and there is little significance for the tautomeric equilibria of the base. The enthalpic term is dominant in the determination of the equilibrium constant.

A theoretical study of tautomerism of 6-thiopurine in the gas and aqueous phases using AM1 and PM3

Heats of formation, entropies, Gibbs free energies, relative tautomerisation energies, tautomeric equilibrium constants, relative proton affinities, dipole moments and ionisation potentials for the eight possible tautomers of 6-thiopurine have been studied using semiempirical AM1 and PM3 quantum-chemical calculations at the SCF level, both in the gas and aqueous phases, with full geometry optimisation. The COSMO solvation model was employed for aqueous solution calculations. The calculations show that 6-thiopurine exists as the thiol–amino forms in the gas phase whereas the thione–amino forms are the predominant tautomers in the aqueous solution. The thione–N(7)H tautomer is more stable than the thione–N(9)H tautomers in aqueous solution. The results are in good agreement with available experimental and theoretical results. The entropy effect on the Gibbs free energy of the 6-thiopurine base is very small and there is little significance for the tautomeric equilibria of the base. The enthalpic term is dominant also in the determination of the equilibrium constant.

A theoretical study of tautomerism of cytosine, thymine, uracil and their 1-methyl analogues in the gas and aqueous phases using AM1 and PM3

Heats of formation, entropies, Gibbs free energies, relative tautomerisation energies, relative proton affinities, tautomeric equilibrium constants, dipole moments, and ionisation potentials for the tautomers of cytosine, uracil, thymine and their 1-methyl analogues have been studied using semiempirical AM1 and PM3 quantum-chemical calculations at the SCF level in the gas and aqueous phases, with full geometry optimisation. The COSMO solvation model was employed for aqueous solution calculations. The calculations show that the oxo-amino or dioxo tautomers are the most stable both in the gas and aqueous phase. The results are in good agreement with the available experimental and theoretical data. The entropy effect on the Gibbs free energy of the pyrimidine bases is very small and there is little significance for the tautomeric equilibria of pyrimidine bases. The enthalpic term is dominant also in the determination of the equilibrium constant.