4- Hydroxypyridines, calculated tautomerism

Repeat your analysis for tautomeric equilibria between 4-hydroxypyridine and 4-pyridone, 2-hydroxypyrimidine and 2-pyrimidone and 4-hydroxypyrimidine and 4-pyrimidone. For each, identify the favored (lower-energy) tautomer, and then use equation (1) to calculate the ratio of tautomers present at equilibrium. Point out any major differences among the four systems and rationalize what you observe. (Hint Compare dipole moments and electrostatic potential maps of the two pyridones and the two pyrimidones. How are these related to molecular stability )... 

Many of the properties oj -hydroxypyridines are typical of phenols. It was long assumed that they existed exclusively in the hydroxy form, and early physical measurements seemed to confirm this. For example, the ultraviolet spectrum of a methanolic solution of 3-hydroxypyridine is very similar to that of the 3-methoxy analog, and the value of the dipole moment of 3-hydroxypyridine obtained in dioxane indicates little, if any, zwitterion formation. However, it has now become clear that the hydroxy form is greatly predominant only in solvents of low dielectric constant. Comparison of the pK values of 3-hydroxypyridine with those of the alternative methylated forms indicated that the two tautomeric forms are of comparable stability in aqueous solution (Table II), and this was confirmed using ultraviolet spectroscopy. The ratios calculated from the ultraviolet spectral data are in good agreement with those de-... 

Hydroxypyridine 1-oxide is insoluble in chloroform and other suitable solvents, and, although the solid-state infrared spectrum indicates that strong intermolecular hydrogen bonding occurs, no additional structural conclusions could be reached. Jaffe has attempted to deduce the structure of 4-hydroxypyridine 1-oxide using the Hammett equation and molecular orbital calculations. This tautomeric compound reacts with diazomethane to give both the 1- and 4-methoxy derivatives, " and the relation of its structure to other chemical reactions has been discussed by Hayashi. ... 

However, as we shall see in the tautomerism section (2.04.4.2), this conclusion must be tempered by the fact that in the gas phase the predominant tautomer is 2-hydroxypyridine. This also affects calculations of bond lengths in pyridin-2-one by Dewar (70JA2929) using a semiempirical SCF MO 7r-approximation given in the final column of Table 4. This will also be discussed again in the tautomerism section (2.04.4). 

The tautomerism of 2-hydroxypyridine in the gas phase has also been studied by microwave spectroscopy using both a conventional spectrometer and a jet-cooled millimeter-wave spectrometer. The spectra attributable to both (Z)-hydroxy tautomer and 2-pyridinone were observed in all cases, the relative abundance being 3 1 in favor of the hydroxy form. No ( )-hydroxy isomer has been detected (93JPC46). The increased stability of the <7,v-hydroxy tautomer compared to the tra/iv-isomer is confirmed by CNDO/2 calculations (AE— 0.64 kcal/mol), whereas the semiempirical effective pair correlation energy method favors the fra/iv-isomer by 0.69 kcal/mol (90BCJ2981). 

Calculations at the SCF/(mixed basis set) level suggest the tautomerization barrier between the dimers to be 10.7-14.3 kcal/mol, which is about three times smaller than the potential energy barrier for a single proton transfer in monomers (84CPL(107)330, 94JST(312)157). The presence of the dimers of 2-hydroxypyridine in the gas phase was confirmed by IR spectra (01SA(A)2659). 

The substituent effects on the prototropic tautomerism of monosubstituted (00PJC1283) and polyhalogenated (99PJC1863) 2-hydroxypyridines in the gas phase have been estimated by semiempirical AMI calculations. 

The effect of benzannulation on the position of the tautomeric equilibrium has been evaluated using the PMO semiempirical calculations (90ZOR1387) and revealed the following trends (a) the transition from 2-hydroxypyridine to 2-hydro-xyquinoline and 1-hydroxyisoquinoline leads to increased stability of the oxo tautomer (b) transition from 2-hydroxypyridine to 3-hydroxyisoquinoline shifts the equilibrium toward the hydroxy tautomer and (c) the relative stability of the oxo tautomer of 1-hydroxyisoquinoline is higher compared to that of 2-hydroxyquino-line. These theoretical results are in good agreement with the experimental data. 

Semiempirical AMI studies of the effect of an additional heteroatom on the tautomeric equilibrium position showed that transition from 2-hydroxypyridines to 3-hydroxypyridazines should shift the equilibrium toward the oxo form (88ZOR1799). Later, semiempirical (AMI, MNDO, and MINDO/3) and ab initio (3-21G basis set) calculations were performed for unsubstituted 3-hydroxypyridazine (90JST(206)295). Whereas ab initio methods correctly predicted the greater stability of the oxo... 

In an ab initio study of the tautomerism of 2- and 4-hydroxy-pyridines, 4,-hydroxypyridine was calculated to be 2.4 kcal/mol more stable than 4-pyridone. 2-Pyridone was calculated to be 0.3 kcal /mol more stable than 2-hydroxypyridine and this is in good agreement with experimental values obtained from tautomeric studies in the gas phase.61 A study of the bromination of the 2-pyridone/2-hydroxypyridine system has revealed that reaction occurs via the principal "one" tautomer at pH<6 and via the conjugate anion at pH>6. Attack on the "one occurs preferentially at the 3-position, whereas on the anion it probably occurs mainly at the 5-position. The facile formation of 3i5-dibromo-2-pyridone results from the comparable reactivity of the monobromopyridones at pH<1 and pH>4- Practical procedures have been reported for the preparation of 3-bromo-2-pyridone and... 

Tautomerizations are also subject to the dictates of equation (16), with the more polar form increasingly favored in more polar media. This has been another successful target for FEP calculations, with applications ranging from 2-hydroxypyridine and histamine to nucleotide bases. In addition, the influence of solvation on simple carbenium ion rearrangements has been investigated by MC-FEP simulations. For the conversion of the classical to the non-classical 2-norbomyl cation in water and that of a tertiary cyclopentylcarbinyl cation to a secondary cyclohexyl cation in methylene chloride and THF, solvation differences of only ca, 1 kcal mol were obtained. Such ions are all relatively charge-delocalized and are consequently immune to significant differential solvation. 

For the first time, such an approach was used by Metzler and collaborators [20] who studied the two-component tautomeric equilibrium between the neutral form (37b, Chapter 1) and the dipolar ion (37a, Chapter 1) of 3-hydroxypyridine in water and water/methanol binary mixtures at various temperatures. Very similar is the procedure used by Reeves et al. [21] for the analysis of the keto-enol tautomerism of 4-phenylazo-l-naphthol-2,4 -disulfonate VSzquez Segura and collaborators [22] in the case of 5 -deoxypyridoxal and Vilanova et al. [23] for the analysis of tautomeric members of vitamin Bg family. In all these cases, the individual bands belonging to tautomers are mathematically resolved using a suitable band-shape function (in this case log-normal [18]), and the corresponding spectral areas I are calculated. The tautomeric constant Kj. is then given as... 

Table 13.3 Calculated 2-hydroxypyridine-pyrid-2(l H)-one (lA-lB) tautomerization energies in aqueous solution.

For many years microwave (MW) spectroscopy has been providing invaluable information about the structure of tautomers in the gas phase. However, more recently, MW spectroscopists have been able to identify several tautomers simultaneously four tautomers of guanine [6] two tautomers of 2-hydroxypyridine/2-pyridone microsolvated with one and two water molecules [7] two tautomers, H and ZH, of 4-vinylimidazole [8] and all five tautomers of cytosine [9]. These data are very useful for theoretical chemists, but reciprocally it should be remembered that MW spectroscopists use high-level theoretical calculations to assign their structures. A cautionary note should be added here about the problem of theoretically calculated entropic contributions and the use of the harmonic approximation [10]. Well-known aspects are the relationships between tautomerism and aromaticity due to the work of some pre-eminent authors Katritzky et al. [11], Schleyer et al. [12], and Krygowski et al. [13]. Another well-understood issue is the influence of intramolecular hydrogen-bonds (IMHBs) on tautomerism [14,15]. 

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