Tautomeric forms, stabilization

An interesting example oftautomerism in sulfamethazine is a recently reported 2 1 cocrystal with theophylline [96]. In this three-component system, the sulfamethazine occurs in both tautomeric forms, stabilized by a rich pattern of hydrogen bonds with the theophylline molecules (Scheme 13.14). Amido tautomer forms R2 (7) hydrogen bond system, where the pyrimidine nitrogen... 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

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-... 

VI. Stabilization of Unusual Tautomeric Forms of Azoles and Their Derivatives... 

Theoretical studies of the relative stabilities of tautomers 14a and 14b were carried out mostly at the semiempirical level. AMI and PM3 calculations [98JST(T)249] of the relative stabilities carried out for a series of 4(5)-substituted imidazoles 14 (R = H, R = H, CH3, OH, F, NO2, Ph) are mostly in accord with the conclusion based on the Charton s equation. From the comparison of the electronic spectra of 4(5)-phenylimidazole 14 (R2 = Ph, R = R3 = H) and 2,4(5)-diphenylimidazole 14 (R = R = Ph, R = H) in ethanol with those calculated by using ir-electron PPP method for each of the tautomeric forms, it follows that calculations for type 14a tautomers match the experimentally observed spectra better (86ZC378). The AMI calculations [92JCS(P1)2779] of enthalpies of formation of 4(5)-aminoimidazole 14 (R = NH2, R = R = H) and 4(5)-nitroimidazole 14 (R = NO2, R = R = H) point to tautomers 14a and 14b respectively as being energetically preferred in the gas phase. Both predictions are in disagreement with expectations based on Charton s equation and the data related to basicity measurements (Table III). These inconsistencies may be... 

A theoretical ab initio study of the gas-phase basicities of methyldiazoles (90JA1303) included a discussion of the 4(5)-methylimidazole tautomer-ism. The RHF/4-31G calculations led to the conclusion that the 4-methyl tautomeric form 14a (R = Me, R = R = H) is 5.2 kJ moP more stable than its 5-methyl counterpart 14b. It was emphasized that this result is to be considered as basic-set dependent. However, a recent theoretical study [94JST(T)45] showed that, starting from the RHF/6-31G level, all the more accurate approximations indicate a higher intrinsic stability for the 4-methyl tautomer. At the MP2/6-31G level, the total energy of the 4-methyl tautomer is 0.7 kJ mol lower than that of the 5-methyl tautomer. Inclusion of solvation effects can, thus, strongly affect the position of the tautomeric equilibrium 14a 14b. Recently, a systematic theoretical study... 

The amino form 66a of 5-pyridylamino-l,2,4-triazole stabilized by two intramolecular hydrogen bonds is the only tautomer observed by the X-ray study of the crystal (90KGS1632). However in DMSO-dg, DMF-d7, and HMPA-di8 solutions, the equilibrium involves three tautomeric forms 66a-66c (Scheme 31) (90KGS1632). 

AHC(S1), pp. 384,385]. For some derivatives of 119 and 120, the relative stability of oxo isomers may be enhanced. Thus, the predominance of the 5,5-diphenyldihydro-4//-l,2,3-triazol-4-one structure 121 in solution has been confirmed by UV and and NMR studies (93CB103). Also, 1-methyl-5-hydroxy-l,2,3-triazole exists mainly in the tautomeric form 120 (R = Me, R = H) [76AHC(S1), p. 385], although the existence of a minor amount of oxo form 122 was postulated to explain the exchange of the 4-position proton in D2O. 

Due to the relatively high acidities of their hydroxy groups, hydroxyazoles readily exchange their protons with metal ions, which leads to stabilization of metal derivatives of the hydroxy tautomeric forms in metal coordination compounds of 2(5)-oxoazoles [97UK434 98AHC(72)1]. A typical example is the mercury complex 361 [93JCS(D)1003]. 

Stabilization of a metal-substituted derivative of a minor tautomeric form of the Ugand was reported for the complexes of mixed benzothiazo-line-benzimidazole (388 —> 389) (71ZOB1370 98POL381) and benzothia-zoline-pyridine ligands (390 —> 391/392) (Scheme 144) (77JA7704). 

MO studies (AMI and AMI-SMI) on the tautomerism and protonation of 2-thiopurine have been reported [95THE(334)223]. Heats of formation and relative energies have been calculated for the nine tautomeric forms in the gas phase. Tire proton affinities were determined for the most stable tautomers 8a-8d. Tire pyrimidine ring in the thiones 8a and 8b has shown a greater proton affinity in comparison with the imidazole ring, or with the other tautomers. In solution, the thione tautomers are claimed to be more stabilized by solvent effects than the thiol forms, and the 3H,1H tautomer 8b is the most stable. So far, no additional experimental data or ab initio calculations have been reported to confirm these conclusions. 

Dipole moments and total energies for pyrazolo[l,5-h]-s-triazole tautomeric forms 97a-97c were calculated using CNDO/2 and CNDO/S (76T341) the results predict the stability of tautomers in a 97a > 97b > 97c sequence. So far, no ab initio calculations or synthesis of 97 have been reported. For pyrazolo[3,2-c]-s-triazole 98 (76T341), the calculated dipole moments, electronic absorption, and proton chemical shifts are in a good... 

The nature of the substituent group X plays an important role in determining the relative stability of the various tautomeric forms. In aliphatic systems the tendency of C—XH to become CH— C 1=X increases markedly in the order X = CHz < NH < O, and certainly hydroxy compounds show less inclination to exist as such than do amino compounds. The position of S in this series is not completely... 

In some cases, one tautomeric form might be expected to predominate because of a greater resonance stabilization for example, the resonance stabilization of 6 should be greater than that of 7 (see following). Chemical evidence has often been adduced for the predominance of one tautomer how-ever, these data must be interpreted... 

Four possible tautomeric forms, e.g., 1,2- (62), 2,3- (63), 1,4- (64), and 2,5- (65), exist for unsubstituted dihydropyrazines however, information on the tautomeric interconversions and stabilities of these forms is sparse. It was demonstrated that, of the four tautomers, 1,4-dihydropyrazine 64 is the least stable (unsubstituted... 

Although 7,14-dihydroxy-6H,13H-pyrazino[l,2- 4,5-,T]bisindole-6,13-dione can jn pr ncipie exist in two tautomeric forms of the dihydroxy compound 39 and the diketo form 40, only the dihydroxy is observed <2003OBC3396>. Presumably this is due to the enolizable 1,3-dicarbonyl moieties and the formation of the indole ring, therefore leading to aromaticity and a net overall stabilization. 

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