Tautomerism equilibria, Table

Sheinker and his collaborators have studied the effect of replacing the hydrogen atoms of the acetamido group with halogen atoms on the tautomeric equilibrium of compounds of this type by using infrared and ultraviolet spectroscopy. Table VII summarizes... 

Quinoxalin-2-ones are in tautomeric equilibrium with 2-hydroxy-quinoxalines, but physical measurements indicate that both in solution and in the solid state they exist as cyclic amides rather than as hydroxy compounds. Thus quinoxalin-2-one and its A -methyl derivative show practically identical ultraviolet absorption and are bases of similar strength. In contrast, the ultraviolet spectra of quinoxalin-2-one and its 0-methyl derivative (2-methoxyquinoxaIine) are dissimilar. The methoxy compound is also a significantly stronger base (Table II). Similar relationships also exist between the ultraviolet absorption and ionization properties of 3-methylquinoxalin-2-one and its N- and 0-methyl derivatives. The infrared spectrum of 3- (p-methoxy-benzyl)quinoxalin-2-one (77) in methylene chloride shows bands at 3375 and 1565 cm" which are absent in the spectrum of the deuterated... 

The alkoxyazocines in Table 1 are in tautomeric equilibrium with their bicyclic or propellanc forms, the equilibrium normally being shifted to the azocine side with the exception of the pentanoazocine 7. In this case, the compound exists as the propellane 6 below 100°C (in tetra-chloroethene), as revealed by NMR spectroscopy, and the azocine form predominates only above 150C. 

On studying a series of ammonium 1,3,2,5-dioxaborataphosphorinane oxides (111), the dependence of the tautomeric equilibrium position on amine basicity was analyzed. The equilibrium position was estimated from chemical shift values of bis(oxymethyl)phenylphosphine oxide with 8 3IP of 35 ppm being used as a model of an acyclic form and 5-Ph-5-oxo-1,3,5-dioxaphosphorinane (107, R = H) with 8 3IP of 6 ppm used as a model of a cyclic compound. The chemical shift values (111, X = 0, R = H) and dissociation constants (pKa) of conjugate acids for amines are presented in Table V. 

The results of some of these techniques are summarized in Table 15 for the situation in pyridin-2-one tautomerism representative results are also included which show how electron withdrawal by insertion of electronegative atoms at position 6 leads to shift of the tautomeric equilibrium towards the hydroxy form. 

Table VII contains the results of the CNDO/2 calculation158 on the energy of cytosine tautomers 2, 3 or 6 and of some derivatives. It can be seen that the calculated energy shifts are in agreement with the effect of substitution on the tautomeric equilibrium of cytosine discussed in Section II, B. Thus, a 5-fluoro substituent causes a small tautomeric shift toward forms 3 (dB i3F Cyt - di ,3t = 2.98 kcal/mole) or 6 (JB l8F Cyt — = 4.87 kcal/mole), while a 6-fluoro substituent...

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. 

The results presented in Table XIX are thus not very unsatisfactory. It would be interesting to calculate the changes in tautomeric equilibrium of uracil on 5- or 6-halo-substitution, particularly the 5-bromo-compound. 

One remarkable feature of these results (Baird and Thomas, 1961) is that the a-protons in the radicals PhNHO and Me3C. NHO give no detectable hyperfine splitting, although the components are quite narrow. It is postulated that either the oxime tautomer is more stable, or that there is a rapid tautomeric equilibrium. In view of the internal consistency of these results (Table 8) it seems probable that the radicals are all of the same form, in which case all that is needed is an acid-base equilibrium sufficiently fast that the lines are not appreciably broadened. 

The products of formal [4 + 2]-cycloaddition between enamines and ( )-l-phenyl-2-nitropropane display the ring-chain tautomeric equilibrium 113A 113B (Table XXI), where the ring form is obtained by intramolecular nucleophilic addition of the N02 group to the enamine C=C bond (86CCA165) (see also 1-222). 

A-2-Thiazoline-5-one may exist in three tautomeric forms (Scheme 108). The tautomeric equilibrium has been studied by H NMR (446. 453. 457. 464), infrared (453. 464-466). and ultraviolet (453, 464) spectroscopies 13C NMR data would be very instructive since model compounds for the three tautomers are now available. Polar solvents favor the enolic (211b) and the mesoionic (211c) forms (Table VII-12), the later being even more favored by high dilution (464). The percentage of the enol... 

In addition to its impact on the biologically active form, the tautomeric process has profound implications for formulation of drug candidates, as illustrated in some recent further development work on compound 3.62 While it is easy to synthesize and isolate water-soluble salts of the keto-acids, once they are placed in aqueous solution the tautomeric equilibrium determines how much of each form is present. Indeed, if the closed butenolide tautomer is sufficiently water insoluble, it can precipitate out of solution and the equilibrium can drive the complete precipitation of the compound. While 3 has good oral activity, its intravenous use is limited by the insolubility of the closed-form butenolide tautomer without the use of a specific and complex buffered formulation. Thus, in recent work Patt et al.62 developed a series of water-soluble butenolides to overcome this limitation for parenteral uses. This culminated in the development of 4 (Table 2), currently in preclinical evaluation. 

The results of the tautomeric equilibrium study of 4(5)-nitroimidazole show that in the gas phase both tautomers have similar energy, but in the solution the 4-tautomer is more stable than the 5-nitro one [256, 1124], The dipole moment of 4(5)-nitroimidazole is practically the same as that of l-methyl-4-nitroimidazole (Table 3.72). 

Ab initio calculated (6-31G ) dipole moments of 3- and 5-nitropyrazoles and their H-complexes and experimentally measured values of l-methyl-3-nitropyrazole (6.20 D, see Table 3.72) show that the tautomeric equilibrium is shifted to 3-nitropyrazole in dioxane [1267], Calculations show that the dipole moments of the molecule and the corresponding H-complexes slightly differ ( 0.2 D) and the difference between the energies obtained for these complexes is 1.1 kcal/mol [1267],... 

IR and UV/Vis [65a], mass spectrometric [65b], photoelectron [65c], microwave [65d], as well as low-temperature matrix-isolation IR spectroscopic measurements [65e] reveal that 2- and 4-hydroxypyridine (as well as 2- and 4-mercaptopyridine [65f]) exist in the gas phase and in inert matrices (N2, Ar) under equilibrium conditions mainly in the lactim (hydroxy or mercapto) form, in contrast to the situation in solution. While in nonpolar solvents such as cyclohexane and chloroform both tautomers exist in comparable amounts, the tautomeric equilibrium is shifted entirely in favour of the lactam (0x0 or thioxo) form in polar solvents such as water, as well as in the crystalUne state [66, 67, 141-145, 251-255], Supercritical-fluid 1,1-difluoroethane can be used to adjust the tautomeric constant Ki = [(llb)]l[(lla)] iso thermally over a continuum from gas-phase values to those measured in polar solvents, simply by increasing the pressure [254]. The gas-phase and solution equilibrium constants of 2- and 4-hydroxypyridine are given in Table 4-4. 

The first attempt to introduce an empirical relationship between an equilibrium constant and solvent polarity was made in 1914 by K. H. Meyer [24]. Studying the solvent-dependent keto-enol tautomerism of 1,3-dicarbonyl compounds, he found a proportionality between the equilibrium constants of various tautomeric compounds in the same set of different solvents cf. Table 4-2 in Section 4.3.1). He therefore split the tautomeric equilibrium constant Ky into two independent factors according to Eq. (7-9). 

Both models mentioned have been used to investigate the simultaneous influence of electronic excitation and solvation (hydration) on the tautomeric equilibrium in the first two excited states of 2- and 4-oxopyri-dine tautomers (2a), (2b) and (3a), (3b). The relative stabilization energies A a,b( ) in the first two excited electronic states of the tautomers in question are given with the available experimental data in Table VIII. Comparison with experimental data can only be done for the second excited state (the appropriate experimental data for the first n - 7r state are not available). In the case of 2-oxopyridine the value of Af2a,2b( ) is estimated to be equal to -(5.4-11.7) kJ mole-1 from shifts of the absorption bands of the lactim and lactam tautomers of 2-oxopyridine and the... 

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