Tautomers, equilibrium constants

To address the shortcomings in FEP results, Worth and Richards used their previously studied system of histamine monocation in aqueous solution and calculated the corresponding tautomer equilibrium constant. The intra-and intermolecular contributions to the relative SFE were evaluated separately ... 

The comparison of the experimental mean values with the theoretically calculated ones for individual tautomers (Section 4.04.1.5.1) (76AHC(S1)1) or conformers (Section 4.04.1.4.3) has been used in the literature to determine equilibrium constants. Thus, the experimental value for l,l -thiocarbonylbis(pyrazole) (40) is 3.19 D and the vector sums of the simple group moments after addition of the extra mesomeric moments are shown in Figure 8. From these values Carlsson and Sandstrom (6SACS1655) concluded that conformation (40b) exerts the largest influence. 

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. 

All the N-unsubstituted pyrazoles (129) in solution (and probably in the gas phase) are mixtures of annular tautomers in different proportions, depending on the nature of the substituents R and R. In the majority of cases the difference of free energy between both tautomers is low enough for the chemical reactivity to be unrelated to the equilibrium constant. 

When R = H, in all the known examples, the 3-substituted tautomer (129a) predominates, with the possible exception of 3(5)-methylpyrazole (R = Me, R = H) in which the 5-methyl tautomer slightly predominates in HMPT solution at -17 °C (54%) (77JOC659) (Section 4.04.1.3.4). For the general case when R = or a dependence of the form logjRTT = <2 Za.s cTi + b Xa.s (Tr, with a>0,b <0 and a> b, has been proposed for solutions in dipolar aprotic solvents (790MR( 12)587). The equation predicts that the 5-trimethylsilyl tautomer is more stable than the 3-trimethylsilylpyrazole, since experimental work has to be done to understand the influence of the substituents on the equilibrium constant which is solvent dependent (78T2259). There is no problem with indazole since the IH tautomer is always the more stable (83H(20)1713). 

Together with pyridones, the tautomerism of pyrazolones has been studied most intensely and serves as a model for other work on tautomerism (76AHC(Sl)l). 1-Substituted pyrazolin-5-ones (78) can exist in three tautomeric forms, classically known as CH (78a), (DH (78b) and NH (78c). In the vapour phase the CH tautomer predominates and in the solid state there is a strongly H-bonded mixture of OH and HN tautomers (Section 4.04.1.3.1). However, most studies of the tautomerism of pyrazolones correspond to the determination of equilibrium constants in solution (see Figure 20). 

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). 

The ultraviolet spectrum of vitamin Be, or pyridoxine, measured in aqueous ethanol varies with the composition of the solvent indicating that this compound is in equilibrium with the zwitterion form 38. The equilibrium constant in pure water was obtained by extrapolation. Prior to this, equilibria which involved tautomers of type 39 had been suggested for vitamin Be, but see Section VI,A. In the case of pyridoxal, an additional equilibrium, 40 41, occurs (cf. Section VIII) other pyridoxal analogs have also been studied (Table II). 

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. 

Contributions in this section are important because they provide structural information (geometries, dipole moments, and rotational constants) of individual tautomers in the gas phase. The molecular structure and tautomer equilibrium of 1,2,3-triazole (20) has been determined by MW spectroscopy [88ACSA(A)500].This case is paradigmatic since it illustrates one of the limitations of this technique the sensitivity depends on the dipole moment and compounds without a permanent dipole are invisible for MW. In the case of 1,2,3-triazole, the dipole moments are 4.38 and 0.218 D for 20b and 20a, respectively. Hence the signals for 20a are very weak. Nevertheless, the relative abundance of the tautomers, estimated from intensity measurements, is 20b/20a 1 1000 at room temperature. The structural refinement of 20a was carried out based upon the electron diffraction data (Section V,D,4). 

A negative value of free energy or energy in quantum chemical calculations corresponds to the tautomer 2a (3-X tautomer) being more stable than 3a (5-X tautomer). The equilibrium constant is calculated as Kj- = 2a/2b. 

It should finally be noted that the amount of the neutral and zweitterionic forms of a compound in solution is determined by its tatuomeric equilibrium constant, defined as Kz = cz/cn. Therefore, the neutral species and the zwitterion coexist around the isoelectric pH, and membrane permeation is conditioned by Kx and by the partition coefficient values of both tautomers. 

The 2-substituted system has proven especially attractive to modelers because the experimental equilibrium constants are known both in the gas phase and in many different solutions. As a result, the focus of the modeling study can be on the straightforward calculation of the differential solvation free energy of the two tautomers, without any requirement to first accurately calculate the relative tautomeric free energies in the gas phase. However, in 1992 Les et al. [290] suggested that prior experimental data [240,266,288], primarily in the form of ultraviolet spectra in the gas phase and in low-temperature matrices, had been misinterpreted and that the reported equilibrium constants referred to homomeric dimers of tautomers (i.e., (42)2 (43)2). Parchment et al. [291] contested this... 

Rate and equilibrium constant measurements for the enolization of 3-phenylcoumaran-2-one (82) in aqueous dioxane indicate an enol content of ca 0.1%, a pKg, of 8.9 (6.0 for the enol tautomer), and a fairly symmetrical transition state for enolate anion formation the Brpnsted Pb = 0.52 Below pH 5, enolization is independent of pH, occurring via O-protonation of the enolate. 

Enolization and ketonization kinetics and equilibrium constants have been reported for phenylacetylpyridines (85a), and their enol tautomers (85b), together with estimates of the stability of a third type of tautomer, the zwitterion (85c). The latter provides a nitrogen protonation route for the keto-enol tautomerization. The two alternative acid-catalysed routes for enolization, i.e. O- versus Af-protonation, are assessed in terms of pK differences, and of equilibrium proton-activating factors which measure the C-H acidifying effects of the binding of a proton catalyst at oxygen or at nitrogen. 

A mechanistic study of acetophenone keto-enol tautomerism has been reported, and intramolecular and external factors determining the enol-enol equilibria in the cw-enol forms of 1,3-dicarbonyl compounds have been analysed. The effects of substituents, solvents, concentration, and temperature on the tautomerization of ethyl 3-oxobutyrate and its 2-alkyl derivatives have been studied, and the keto-enol tautomerism of mono-substituted phenylpyruvic acids has been investigated. Equilibrium constants have been measured for the keto-enol tautomers of 2-, 3- and 4-phenylacetylpyridines in aqueous solution. A procedure has been developed for the acylation of phosphoryl- and thiophosphoryl-acetonitriles under phase-transfer catalysis conditions, and the keto-enol tautomerism of the resulting phosphoryl(thiophosphoryl)-substituted acylacetonitriles has been studied. The equilibrium (388) (389) has been catalysed by acid, base and by iron(III). Whereas... 

Drug molecules frequently contain functional groups such as amines and carboxylic acids that are ionized under normal physiological conditions. Typically, these are registered in databases in their neutral forms that are perfectly reasonable when the main objective is efficient retrieval of structures. Representation of tautomers [6, 7], which differ only in bond type and hydrogen atom connectivity, raises similar issues while measurement of the relevant equilibrium constants is significantly more difficult. 

The most powerful method currently available for the quantitative determination of ring-chain equilibrium constants is H-NMR spectroscopy. Often, two pairs of indicator signals of both tautomeric forms have been used, thereljy increasing the accuracy of equilibrium-constant determination. For structural analysis of the tautomers and quantitative measure-... 

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