Tautomeric Ratios Research Articles

Neutral hosts for the complexation of creatinine

Three hydrogen bonds are formed between creatinine and derivatives of 2-amino-4(3 H)pyrimidone. Changes in the tautomer ratio of the latter upon complexation can be observed by UV spectroscopy. The formation of a further hydrogen bond between creatinine and a 4-aminoacridin-5-yl-amino-substituted 4(3 H)pyrimidone seems to be sterically prevented. The properties of three other, quite different compounds assumed to form three hydrogen bonds with creatinine have also been investigated. Dodecyl 4-octadecylallophanate and 2,6-bis(dodecylamino)-pyridine do not associate appreciably with creatinine, which can be explained by the formation of an intramolecular hydrogen bond in the former compound and the lack of tautomerization of the latter. With 6-(1-heptyloctylamino)-2(1 H)-pyridone, however, creatinine forms a complex that is almost as stable as those with 2-amino-4(3 H)-pyrimidone derivatives.

Ring-chain tautomerism of oxazolidines derived from serine esters

In spite of an earlier statement (Bull. Chem. Soc. Jpn. *1981, 54, 1844), ring-chain tautomeric mixtures were obtained from serine methyl or ethyl ester with aromatic aldehydes. Tautomeric ratios gave a good correlation according to the equation log K = ϱσ + + log K 0. A clear tendency was also found between the tautomeric ratios and the dielectric constants of the solvents.

Base mismatches and mutagenesis: how important is tautomerism?

The majority of mismatches have C 1′-C 1′ distances that are very close to the standard distance found in Watson-Crick base pairs. This means that there is minimal disturbance of the double helix, which in any case is very variable in detail 16. If the C 1′-C 1′ distance is the most important geometrical facet of the bases, then it seems likely, since a pyrimidine or purine itself presents a very different geometry, that the enzyme can cope with any difference in the backbone due to its inherent flexibility. Tautomerism cannot be excluded but it would seem that it is the harder case to prove. What is needed now are accurate measurements of tautomer ratios by modern techniques. The older values were recognized at the time to be very approximate because of inherent assumptions. This review will hopefully stimulate research in understanding the slow majestic pace of evolution at the molecular level.

Substituent effects on the ring-chain tautomerism of 1,3-oxazines

The aryl substituents at positions 4 and 6 do not exert observable electronic effects on the ring-chain tautomeric ratios of 2,4- or 2,6-diarylsubstituted-tetrahydro-1,3-oxazines. On the other hand, the electronic effect of the 2-aryl substituent is marked: in all eight series studied, the equilibria can be described by the equation log K = ϱ σ + +log K 0, where ϱ + is the Hammett-Brown constant of the 2-aryl substituents, and ϱ is a constant characteristic of the ring system (=0.75±0.05).

Pterin 1H–3H tautomerism and its possible relevance to the binding of folate to dihydrofolate reductase

Ab initio and free energy perturbation calculations show that the 1H:3H tautomer ratio is 1 :6 for pterin in aqueous solution, implying that the 1H tautomer of folate may be responsible for non-productive binding to dihydrofolate reductase.

Theoretical interpretation of the gas phase equilibrium of 2-hydroxypyridine/2(1 H)-pyridinone

Theoretical ab initio calculations are performed to provide support for our hypothesis that the gas phase ratio of the 2-hydroxypyridine/2(1 H)-pyridinone tautomers results from the thermodynamic equilibrium which exists between cyclic hydrogen-bonded oxo-oxo and hydroxy-hydroxy dimers. We therefore, disprove the monomolecular mechanism of the tautomerization process, which has frequently been assumed in the past to estimate the free energy difference between the monomeric tautomers based on the experimentally determined tautomer ratio.

Synthesis and duplex stability of oligonucleotides containing adenine-guanine analogues

The nucleosides N6-methoxy-2′-deoxyadenosine (dZ) and 2-amino-9-(2-deoxy-β-ribofuranosyl)-6-methoxyaminopurine (dK) have been synthesised and converted into 5′-O-dimethoxytrityl 3′-(2-cyanoethyl N,N-diisopropylphosphoramidites). These monomers have been used in machine DNA synthesis to give a set of heptadecanucleotides containing up to three analogue nucleotides. The melting transitions (Tm) show that the 17-mer duplexes containing Z·T and Z·C base-pairs have closely similar stabilities, as have those containing K·T and K·C pairs. They are less stable than the corresponding fully complementary duplexes, but more stable than those contianing mismatched pairs. This, in the case of dZ, is in accord with the amino-imino tautomeric ratio of ∼1:4 observed for the nucleoside in methylsulfoxide. The application of oligomers containing such “degenerate” bases in oligonucleotide probes and primers is discussed.

Studies of Tautomerism in 2-Hydroxynaphthaldehyde Schiff Bases by Multinuclear Magnetic Resonance

Abstract The tautomerism in a Schiff base formed from 2-hydroxynaphthaldehyde and p-methyl aniline has been investigated using multinuclear magnetic resonance techniques. 1H and 13C resonances have been assigned and chemical shifts tabulated. The proportions of the tautomers have been obtained from 1JNH both from direct 15N NMR and from 1H detected 15N spectroscopy and from 3JCH-NH coupling constants and these have been supported by UV spectroscopic measurements. The temperature and solvent dependence of the equilibrium have been investigated and the ketoamine tautomer shown to have a lower free energy than the phenolimine tautomer in CDCI3 solution by approximately 1 KJ.mol−1 at 273K. ΔH and ΔS have been determined from the temperature dependence of the equilibrium constant. The 13C chemical shifts of some of the carbons are very dependent on the proportions of the tautomers and can be used to estimate tautomeric ratios in solvents where no couplings are observed because of exchange processes.

Studies of tautomerism and protonation in 2‐aryl‐1H‐imidazo[1,2‐a]imidazole derivatives using 1H and 13C NMR

AbstractThe tautomerism and protonation of the putative inotropic 2‐(2′,4′‐dimethoxy)phenyl‐1H‐imidazo[1,2‐a]imidazole (2) has been studied in several solvents by comparing its 1H and 13C chemical shifts with those of its 1‐ and 7‐methyl derivatives 3 and 4, respectively, and acid salts. Tautomer and rotamer populations were also estimated from measurements of proton relaxation rates and NOE effects. Heterocycle 2 exists predominantly as the 1H‐tautomer in CDCl3, but as the 7H‐tautomer in DMSO‐d6 and methanol‐d4–D2O solutions. In CDCl3 solution, 2 appears to exist with the N‐1‐H and 2′‐OMe groups adjacent, but in DMSO‐d6 the conformation is the rotated form with N‐7‐H and H‐6′ adjacent; 3 exists as a mixture of rotamers in CDCl3 and in DMSO‐d6 whereas 4 is in the form with the N‐7‐Me and H‐6′ adjacent in both solvents. The observed conformational preferences have been compared with the results of semi‐empirical molecular orbital calculations and found to be in broad agreement. Protonation of 2 occurs mainly at N‐1 in DMSO‐d6 and at N‐7 in CDCl3, as expected from observed tautomeric ratios in the free base.

Free Energy Calculations of Pharmaceutically Important Properties

Abstract When determining the biochemical function of a proposed new drug it is useful to be able to calculate a number of properties which regulate its behaviour. By using the Free Energy Perturbation method incorporated into molecular dynamics, both on its own and in conjunction with quantum mechanical calculations, we have calculated redox potentials, pKa s, tautomer ratios and partition coefficients on model systems. This paper reviews the techniques currently being used to perform such calculations and presents the results for a number of different systems. The accuracy with which the properties are determined is most encouraging and suggests that useful calculations on realistic systems are now possible, and will play a major role in drug-design in the future.

Histamine tautomerism and its mode of action

An established combination of quantum mechanical calculations and molecular dynamics simulations (Worth, C.A., King, P.M. and Richards, W.G. (1989) Biochim. Biophys. Acta 993, 134–136; Cieplak, P., Singh, U.C. and Kollman, P.A. (1987) Int. J. Quant. Chem. QBS14, 65–74; Reynolds, C.A., King, P.M. and Richards, W.G. (1988) Nature 334, 80–82) has been used to calculate the tautomer ratios of histamine species in aqueous solution. The results are in good agreement with experiment and provide a bridge between experimental data and earlier theoretical calculations.

ChemInform Abstract: The Tautomerism of 1,2,3‐Triazole in Aqueous Solution.

Two circumstantial but independent arguments both confirm that the 2H-tautomer of 1,2,3-triazole is favoured in aqueous solution by a factor of ca. two. Lone-pair repulsion is the probable cause; evidence from the solvent dependence of the tautomeric ratio is discussed.

α-D-Glucopyranosyl-D-fructoses: distribution of furanoid and pyranoid tautomers in water, dimethyl sulphoxide, and pyridine. Studies on ketoses. Part 4

The tautomeric distributions of trehalulose (2), turanose (3), maltulose (4), leucrose (5), and palatinose (6) have been established using an 1H NMR methodology based on integration of the low-field anomeric OH singlets in dimethyl sulphoxide. Equilibration in dimethyl sulphoxide being exceedingly slow the method can be applied to determine tautomeric ratios in essentially any solvent, by freezing a small probe of the respective solution (liquid N2), dissolving the resulting ice-matrix in (CD3)2SO and rapid recording of the intensities in the low-field OH-region. In dimethyl sulphoxide, fructose, trehalulose (2), turanose (3), and maltulose (4) adopt equilibria with a high proportion of the furanoid tautomers (∼ 60% at 20 °C) in an approximate 2:1 β-f/α-f-ratio versus 10:1 for the β-p/α-p-forms. For leucrose (5), the β-p⇌α-p equilibrium lies at the β-p side with a 9:1 preference, whereas palatinose (6) establishes an 11 :4 β-f⇌α-f equilibrium with a comparably high proportion of the acyclic keto-form (6%), that, in all other cases, is ⩽ 1%. There is little temperature dependence of the anomeric compositions in the 20–70 °C range. In water, the β-p form invariably is the most abundant at equilibrium, decreasing substantially though with rising temperature in favour of the β-fand α-f-tautomers. The equilibrium compositions of fructose, trehalulose, and maltulose being almost identical, that of turanose is markedly shifted towards higher proportions of furanoid forms, amounting to two-thirds of the mixture at 70 °C. Aqueous solutions of leucrose contain the β-p form almost exclusively, palatinose establishes a 5:1 to 3:1 β-f⇌α-f equilibrium over the 1–70 °C range. In pyridine, equilibrium tautomeric compositions are similar to those found for water, except for distinctly slower tautomerization rates. The preparative implications for derivatizations of these glycosyl-fructoses in pyridine are discussed, their now predictable outcome being strongly dependent on the mode of dissolution of the substrate, and the temperature of the reaction.

Theoretical calculation of tautomer equilibria in solution: 4-(5-)methylimidazole

A combination of quantum mechanical calculations and molecular dynamics simulations has been used to calculate the tautomer ratio of 4-(5-)methyl imidazole in solution, and the results are in good agreement with experiment.

Thermochemical Investigations of Tautomeric Equilibrium. Variation of the Calculated Equilibrium Constant with Binary Solvent Composition

Abstract A conventional nonelectrolyte solution model which has led to successful predictive equations for solute solubility and infinite dilution chromatographic partition coefficients is extended to systems containing a tautomeric solute dissolved in a binary solvent mixture. The derived expression predicts that the tautomeric solute concentration in a binary solvent is a geometric average of the pure solvent ratios and permits calculation of solute-solvent association constants from variation of the stoichiometric tautomeric solute concentration ratios as a function of binary solvent composition. Experimental data for phenylazonaphthol dissolved in aqueous-ethanol and aqueous-acetone solvent mixtures is discussed in relation to the theoretical model.

A selective synthesis of 1‐aryl‐3‐quinoxalinyl‐1,2,4‐triazole and furo[2,3‐b]quinoxaline

AbstractThe reaction of the ester 1 with ethyl benzoate‐2‐diazonium chloride gave the α‐arylhydrazonoester 2b, whose reaction with hydrazine hydrate afforded the α‐arylhydrazonoacylhydrazide 3b. The reaction of 3b with sodium nitrite in water/acetic acid under heating on a boiling water bath provided the 1‐aryl‐3‐quin‐oxalinyl‐1,2,4‐triazole 5b, presumably via the α‐arylhydrazonoacylazide 4b, while the isolation of 4b and then its refluxing in dioxane/water furnished the furo[2,3‐b]quinoxaline 6. The tautomeric behavior of 2b and 3b between the hydrazone imine and diazenyl enamine forms was described together with the tautomer ratio determined by the nmr spectral data.

Synthesis and tautomeric behavior of 3‐(pyrazolylhydrazonomethyl)‐2‐oxo‐1, 2‐dihydroquinoxalines. Specification of hydrazone imine and diazenyl enamine forms

Abstract3‐(Pyrazolylhydrazonomethyl)‐2‐oxo‐1, 2‐dihydroquinoxalines were synthesized, and their tautomer ratios between hydrazone imine and diazenyl enamine forms were specified by pmr spectral data.

The tautomerism of 1,2,3-triazole in aqueous solution

Two circumstantial but independent arguments both confirm that the 2H-tautomer of 1,2,3-triazole is favoured in aqueous solution by a factor of ca. two. Lone-pair repulsion is the probable cause; evidence from the solvent dependence of the tautomeric ratio is discussed.

Tautomerism in 2-ketomethyl quinolines

The i.r.solution spectra of a series of 2-ketomethylquinolines have been studied. Tautomeric ratios have been determined by n.m.r. spectroscopy. With one exception the compounds were substantially or exclusively in the enaminone forms. The only compound carrying an α-methyl group (18) proved to be solely in the ketone form.

Semiempirical MNDO study of the tautomerism in 3-substituted tetronic acids

The relative stabilities of tautomers of 3-acetyl- ( 1), 3-formyl- ( 2) and 3-nitrotetronic ( 3) acids are calculated by using the MNDO approach. Estimated thermodynamic parameters indicate that for 1 and 2 the ex—enol tautomeric pair b ⇌ d is ca. 5 kcal mol −1 more stable than the corresponding endo—enol tautomers. In contrast, end—enol tautomers (a ⇌ c) of 3 appear to be more stable by ca. 3 kcal mol −1 relative to their exo — enol counterparts. Differences in total energies of tautomers are elucidated by the energy partitioning technique. The role of solvation is briefly discussed at a qualitative level. If the solvation effects are taken into account the ratios of tautomers is in qualitative accordance with NMR measurements.