Tautomeric ratios

The rate of the equilibrium is greatly accelerated upon addition of an acid (e.g., CF3COOH) [86MRC444 94JCS(P2)1561], although this does not affect the tautomeric ratio. 

Takacs-Novak, K., Tam, K. Y. Multiwavelength spectrophotometric determination of add dissodation constants. Part V. Microconstants and tautomeric ratios of diprotic amphoteric drugs./. Pharm. Eiomed. Anal. 2000, 17, 1171-1182. 

Niflumic acid, which has two pKa values, was studied both pH-metrically and spectroscopically using the shake-flask method [224]. The monoprotonated species can exist in two forms (1) zwitterion, XH 1 and (2) ordinary (uncharged) ampholyte, XH°. The ratio between the two forms (tautomeric ratio) was measured spectroscopically to be 17.4. On assuming that a negligible amount of zwitterion XH partitions into octanol, the calculated micro-log/1 for XH° was 5.1, quite a bit higher than the macro-log/1 3.9 determined pH-metrically in 0.15 M NaCl. It is noteworthy that the distribution coefficient D is the same regardless of whether the species are described with microconstants or macroconstants [275]. 

Although the tautomeric ratios of the 4 species have not been measured directly, it is known that in aqueous solution the keto-N2H form dominates, while the keto-NlH form is only detectable in non-polar solvents. An analysis of experimental data concluded that in aqueous solution the stability (lowest free energy) is in the order keto-N2H > imino-N2H > enol-NlH > keto-NIH. In the gas phase, calculations predict that the keto-N2H form is the least stable. While solvation is found to favour this species, which is the most polar, this stabilisation is not enough to reverse the order of stability. It is thus clearly predicted that the keto-NIH tautomer is the most stable in... 

Pd(0)-catalyzed allylations of 4(5)-nitroimidazole, 2-methyl-4(5)-nitroimidazole, 4(5)-bromoimidazole and 4(5)-methoxyimidazole resulted in complicated mixtures, which did not necessarily reflect the tautomeric ratios of the starting material [7], For example, poor regioselectivity for the products (70 and 71) was observed in the Tsuji-Trost reaction of 4(5)-bromoimidazole with cinnamyl carbonate. However, the same reaction with 4(5)-nitroimidazole and 2-methyl-4(5)-nitroimidazole led predominantly to the l-allylation products. In addition, removal of the 77-imidazole allyl groups can be selectively effected under mild conditions by Pd-catalyzed ic-allyl chemistry [55],... 

Both single and double cyclizations of the Schiff bases 65A and 66A occur in the multicomponent tautomeric mixtures derived from as- and /ra t-cyclohexane aminodiols 69 and 70, to give monocyclized ring forms of C-2-epimeric perhydro-l,3-benzoxazines (B and G) and oxazolidines (D and E), besides 7,ll-dioxa-9-azatricyclo[7.2.1.0 °]-dodecane diastereomers 67 and 68 (Scheme 10). The tautomeric ratios are found to satisfy by Equation (1) (Table 1) and are influenced by the cis- or rra t-geometry of the cyclohexane substituents in the Schiff base (A). For the equilibria... 

As a further interesting extension of the ring-chain tautomeric concept, 2-aryl-l,4-dihydro-2/f-3,l-benzoxazines encapsulated in a cage macromolecule exhibited different tautomeric ratios inside the cavity than those measured in deuterated mesitylene solution <2006JA9308>. 

The tautomeric ratios characterizing the complex scheme of tautomeric conversions of cytosine have not been evaluated. The only quantitative results concern the relative contributions of structures 2,... 

However Morita and Nagakura104 concluded from similar studies that in aqueous solution cytosine exists as an equilibrium mixture of two forms, 2 and 6, only. According to these authors the first form predominates in trimethyl phosphate and water at room temperature, but the second prevails at high temperature. The imine form is considered to predominate also in acetonitrile. From the temperature dependence of the absorption spectrum of cytosine in aqueous solution, Morita and Nagakura estimated the tautomeric ratios Kf-e to be equal to 33, 14, and 8 at 30, 50, and 70°, respectively. The energy115 and entropy differences between the imine form 6 and the amine form 2 were evaluated as 5.5 kcal/mole and 12 cal/mole. deg., respectively. 

The tautomeric ratio of 25 in water for 5,6-dihydrocytosine should be compared with the value of 105 for cytosine itself (see Table II). It thus appears that the hydrogenation of cytosine causes a substantial shift toward the imine form. A further shift toward the imine is observed when 5,6-dihydrocytosine is substituted at the amino group by a hydroxy group. It was shown124 by UV spectra that 1-alkyl-substituted A4-hydroxy-5,6-dihydrocytosines exist in aqueous solution in the lactam(ox)imine form 20. 

The tautomeric ratios characterizing the whole complex scheme of uracil cannot be evaluated. Only the tautomeric equilibrium constant Kt32,28 for uracil was calculated by Katritzky and Waring.97 The ionization constants determined by two different methods (see Table XVII) give the values of 104° and 103 3 for X,32,28 of 1-methyluracil. 

It should be added that Snyder et al.36i have predicted by means of nonempirical calculations that thymine anion 34 should be more stable than 35 in the gas phase by 21 kcal/mole. It is difficult, however, to compare this figure with tautomeric ratios of the thymine anionic forms in aqueous or in dioxan-water solution. 

The equilibrium constant for a tautomeric interconversion is simply the ratio of the mole fractions of the two forms for example, the ratio of enol to oxo forms of acetone12 in water at 25°C is 6.0 x 10 9, while that for isobutyraldehyde is 1.3 x ICE4. The ratio of 2-hydroxypyridine to 2-pyridone is about 10 3 in water but increases to 0.6 in a hydrocarbon solvent and to 2.5 in the vapor phase.13 14 The ratio of dipolar ion to uncharged pyridoxine (Eq. 2-5) is 4 at 25°C in water.15 The ratios of tautomers B, C, and D to the tautomer A of uracil (Eq. 2-4) are small, but it is difficult to measure them quantitatively.16 These tautomeric ratios are defined for given overall states of protonation (see Eq. 6-82). The constants are independent of pH but will change if the overall state of protonation of the molecule is changed. They may also be altered by... 

The tautomeric ratio of B to A for histidine in water (Eq. 2-6) has been estimated, using 15N- and 13C-NMR, as 5.0 when the a-amino group is proto-nated and as 2.5 when at high pH it is unprotonated.17 This tautomerism of the imidazole group is probably important to the function of many enzymes and other proteins for example, if Ne of structure A (Eq. 2-6) is embedded in a protein, a proton approaching from the outside can induce the tautomerism shown with the release of a proton in the interior of the protein, perhaps at the active site of an enzyme. The form protonated on Ns (B of Eq. 2-6), which is the minor form in solution, predominates in some positions within proteins.18... 

The two monoprotonated forms of pyridoxine are the tautomeric pair shown in Eq. 6-75 and whose concentrations are related by the tautomeric ratio, R = [neutral form]/[dipolar ion], a pH-independent equilibrium constant with a value of 0.204/0.796 = 0.26 at 25°C.75 Evaluation of microscopic constants for dissociation of protons from compounds containing non-identical groups depends upon measurement of the tautomeric ratio, or ratios if more than two binding sites are present. In the case of pyridoxine, a spectrophotometric method was used to estimate R. 

To calculate microscopic constants from stepwise constants and tautomeric ratios, consider Eq. 6-76 in which [HP]a and [HP]B are the concentrations of the two tautomers and kj is the first stoichiometric or macroscopic dissociation constant for the diprotonated species H2P. 

Because it is usually difficult to measure tautomeric ratios, dissociation constants are frequently assumed identical to those of compounds in which one of the acidic groups has been modified by methylation or esterification or in some other manner to prevent dissociation of a proton. For example, the cation of 1-methyluracil can be dissociated to the two tautomers shown in Eq. 6-83. 

Thioacetylacetone is a 66 34 mixture of CH3C(OH)=CHC(=S)CH3 and CH3C(=0)CH=C(SH)CH3 tautomers.118 If the CH3 attached to CS is replaced by CD3, the proportion of SH tautomer increases, whereas if the CH3 attached to CO is replaced by CD3, the proportion of SH tautomer decreases. Because both tautomers have the same conjugate base, these changes of tautomeric ratio mean that the relative acidity of the tautomers is changed by the isotopic substitution. Similar behavior is seen with C6D5C (OH)=CHC(=S)C6H5. 

Equilibrium Ring-Chain Tautomeric Ratios for 4-Imino-4//-PYRIDO[l,2-a]PYRIMIDINE-3-CARBONITRILE 167 168 (R = R1 = H) IN DIFFERENT... 

Reaction of the parent triazine (98) with NH4OH in the presence of K3Fe(CN)6 gave the 8-hydroxy compound (38) (10%). Triazine (98) also reacted with dimethyl malonate to deliver a 30% overall yield of an 8-substituted compound, shown to exist as the tautomeric forms (99) and (100). In CDC13 solution the tautomeric ratio between compounds (99) and (100) is 30 70 (Equation (2)) <92CJC2828>. 

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