Tautomerism equilibrium constant

The mean chemical shifts of A- unsubstituted pyrazoles have been used to determine the tautomeric equilibrium constant, but the method often leads to erroneous conclusions (76AHC(Sl)l) unless the equilibrium has been slowed down sufficiently to observe the signals of individual tautomers (Section 4.04.1.5.1). When acetone is used as solvent it is necessary to bear in mind the possibility (depending on the acidity of the pyrazole and the temperature) of observing the signals of the 1 1 adduct (55) whose formation is thermodynamically favoured by lowering the solution temperature (79MI40407). A similar phenomenon is observed when SO2 is used as solvent. 

The use of UV spectroscopy as an identification method is continuously decreasing in relative importance compared to the use of NMR or mass spectrometry. However, due to the general validity of Beer s law, it continues to be an appropriate method for quantitative studies such as the measurement of ionization constants (Section 4.04.2.1.3(iv) and (v)) and the determination of tautomeric equilibrium constants (Section 4.04.4.1.5). 

In a neutral azole, the apparent rate of formation of an A-substituted derivative depends on the rate of reaction of a given tautomer and on the tautomeric equilibrium constant. For example, with a 3(5)-substituted pyrazole such as (199), which exists as a mixture of two tautomers (199a) and (199b) in equilibrium, the product composition [(200)]/[(201)] is a function of the rate constants Ha and fcs, as well as of the composition of the tautomeric mixture (Scheme 16) <76AHC(Si)l). 

One interesting problem frequently recurring in heterocyclic chemistry, particularly with respect to nitrogen heterocycles, is tautomeric equilibria. Too many methods are available for the elucidation of equilibrium positions and tautomeric equilibrium constants (Kj) to adequately review the whole question here. However, the Hammett equation provides one independent method this method has the advantage that it can be used to predict the equilibrium position and to estimate the equilibrium constant, even in cases where the equilibrium position is so far to one side or the other that experimental determination of the concentration of the minor component is impossible. The entire method will be illustrated using nicotinic acid as an example but is, of course, completely general. 

Thus, estimates of tautomeric equilibrium constants are available without any experimental data except the necessary a- and p-values. 

It is well accepted that tautomerism relates to the equilibrium between two or more different tautomers e.g., it corresponds to determining if the structure of a compound is, for instance, a pyridone or an hydroxypyridine. The kinetic aspects are often neglected and when the tautomeric equilibrium constant, Kt, is equal to 1 (e.g., for imidazole), the problem may seem... 

Since the domain explored will always be a very small part of the possible cases of tautomerism, it is essential to have general rules for families of compounds, substituents, and solvents. This chemical approach is maintained in this chapter, although the importance of the calculations is recognized. The following discussion begins with calculation of tautomeric equilibrium constants, followed by the combined use of theoretical calculations and experimental results (an increasingly expanding field) and ends with the calculations of the mechanisms of proton transfer between tautomers. 

Tautomeric Equilibrium Constants Kt = [ll/]/[21/] OF Substituted Tetrazoles 27 in DMSO Estimated from NMR Studies... 

ITIES interface between two immiscible electrolyte solutions K tautomeric equilibrium constant between the zwitterionic and the neutral forms of a compound... 

When determining the tautomeric equilibrium constant for a process... 

Figure 3. Variations of the tautomerism equilibrium constant Kr ([B] = 0.3 mole l 1, 30°C) of t-butyl-2-picolyl (0) and quinaldyl (A) ketones vs. solvent polarity. (DME) dimethoxyethane (CFG) propyleneglycol carbonate (NMF) N-methylformamide (F)formamide.

Medium Effect on the Tautomeric Equilibrium Constant of the Cations of p-Amino- and p-Dimethylamino-derivatives of Azobenzene (Korolev and Titova, 1971)... 

It has been shown by thermodynamic calculations (89TH1) that, under equal structural conditions, the ratio of the tautomeric equilibrium constants for the reversible addition reaction of the SH group and that for the OH group should be 10 in favor of the sulfur addition product. A similar result (>10 ) was estimated (90T6545) from a comparison of the stability of the 1,3-thiazolidine ring with that of the 1,3-oxazolidine ring. 

In particular, when two tautomers HA and AH form the common cation HAH+, the tautomeric equilibrium constants KT can be expressed through the basicity constants KB and KA of these tautomers KT = KA/KB. Since... 

Prototropic tautomerism of 2-alkylated tetrahydro species 21 is solvent dependent, tautomers 21a and 21b being identified as the major species present in DMSO-dimethyl sulfoxide) and deuterochloroform, respectively <2000HCA1693> by NOE experiments. Acetylated analogue 22 appears to behave similarly, although in this case the spectrum is complicated by the presence of amide rotamers. As judged from the N-H signals observed in H NMR spectrum, the major species in deuterochloroform is 22a, whereas, in DMSO-i4> the tautomeric equilibrium constant approaches unity, and both tautomers are present. 

It must be stressed that a statement that benzotriazole protonates on N(3) or that l-methyl-4-aminopyrazole does on the amino group, means only that this is the dominant species in an equilibrium. Experimentally, the tautomeric equilibrium constant between cations can be determined by the general methods used to study tautomerism. Even pK s can be used, if the second protonation of quaternary salts as fixed derivatives are measured. 

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. 

Claramunt et al. [22] used a H and 13C NMR to study the tautomer-isim of omeprazole in solution. The tautomeric equilibrium constant, KT = 0.59 in tetrahydrofuran at 195 K, is in favor of the 6-methoxy tautomer. The assignment of the signals was made by comparison with its two N-methyl derivatives in acetone-d6 and through theoretical calculations of the absolute shieldings (GIAO/DFT/6-3111++G ). 

The relationships between tautomeric equilibrium constants and intramolecular hydrogen bonds (IMHB) are well documented. As expected, an IMHB stabilizes the tautomer that presents it in comparison with other tautomers without IMHB. On the other hand, information about the effect of intermolecular hydrogen bonds on the thermodynamic aspect of tautomerism is scarce. These HBs are of paramount importance in the solid state in solution, the situation is more complicated because there are several possible associations that exist in dynamic equilibrium. For this reason we devoted a theoretical paper to this question, studying homo- and heterodimers of 2-pyridone (63, 64, 65) and 2-aminopyridines (66, 67, 68) [84], In the case of pyridone the most stable dimer is 63 for 2-aminopyridine, it depends on the nature of R. 

Scheme 8 Estimation of the aromaticity of 2-pyridone using tautomeric equilibrium constants.

The tautomerism of 3-mcthyl-v-triazolo[4,3-a]bcnzi midazole 106 was established from the 13C-chemical shifts (in DMSO-d6) of the parent compound and its N-methylated derivatives (78BSF273). Tautomers 106a and 106b are both present in DMSO, whereas 106a is predominant in ethanol and 106b in dioxane (UV spectroscopy) (75JHC197). The interpolation of 13C-chemical shifts was suggested for calculations of tautomeric equilibrium constants. 

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