Tautomerism compounds

The spectra of pyrazolinones have been used in tautomeric studies (Section 4.04.1.5.2). The chemical shifts shown in Table 11 are representative of the three classes of fixed derivatives [OR (63) and (64), NR (65) and CR (66)], and many others are discussed in (76AHC(Sl)l). Some tautomeric compounds are also included in Table 11. 

Fonnanilide is a tautomeric compound, z. c., it reacts as though it possessed the alternative formula ,... 

The whole concept of direct methylation has recently been critically reviewed and rejected by Gompper as a method to study tautomerism. The difference in the proportions of the two methyl derivatives produced w hen diazomethane is in excess, or the reverse, has now been ascribed to the relative importance of the Sn and Sn reactions of the tautomeric compound with diazomethane. The proportions of N- and 0-methyl derivatives formed by the reaction of cyclic amides with diazomethane has been related to the infrared vC—O frequencies. ... 

The determination of pi a values is probably the most generally useful method for the investigation of tautomerism. This method was first employed in the heterocyclic field in the early 1950 s by Tucker and Irvin and by Angyal and Angyal. There are two empirical dissociation constants, and K2, for the conjugate acid (HXH+) of a tautomeric compound. Constants Kt and K2 are, in effect, a summation of the true dissociation constants Ka, Kb, Kc, and Kd of the individual tautomeric forms (see scheme 43, where XH and HX are tautomers) and the tautomeric constant, Kt] these constants are related by the following equations ... 

The electronic spectrum of a compound arises from its 7r-electron system which, to a first approximation, is unaffected by substitution of an alkyl group for a hydrogen atom. Thus, comparison of the ultraviolet spectrum of a potentially tautomeric compound with the spectra of both alkylated forms often indicates which tautomer predominates. For example, Fig. 1 shows that 4-mercaptopyridine exists predominantly as pyrid-4-thione. In favorable cases, i.e., when the spectra of the two alkylated forms are very different and/or there are appreciable amounts of both forms present at equilibrium, the tautomeric constant can be evaluated. By using this method, it was shown, for example, that 6-hydroxyquinoline exists essentially as such in ethanol but that it is in equilibrium with about 1% of the zwitterion form in aqueous solution (Fig. 2). 

This method is not applicable if the spectra of the potentially tautomeric compound and both alkylated derivatives are very similar, e.g., it is not suited to an investigation of the tautomerism of 4-aminopyridine 1-oxide (Fig. 3). A further limitation is that often only qualitative conclusions can be drawn because no contribution from the spectrum of the minor constituent can be found in the spectrum of the tautomeric compound. It should also be noted that, un-... 

If the ultraviolet spectra of a potentially tautomeric compound and of both alkylated derivatives are too similar to allow conclusions to be drawn regarding their structures, sometimes fluorescence spectra can be used instead. By using this technique, Gompper and Her-linger showed that 4,5-diphenyloxazol-2-one (53) does, indeed, exist in the 2-oxo form. 

Attempts have been made to deduce the structure of the predominant form of a potentially tautomeric compound from the shifts which occur in the ultraviolet spectrum of the compound in question on passing from neutral to basic or acidic solutions. The fact that no bathochromic shifts were observed for 2- and 4-hydroxy quinoline and 1-hydroxyisoquinoline under these conditions was taken as evidence that they existed in the oxo form [similar work on substituted quinol-4-ones led to no definite conclusions ]. A knowledge of the dissociation constants is essential to studies of this type, and the conclusions can, in any case, be only very tentative. A further dif-... 

The pKa values of 4-hydroxypyridine 1-oxide (51 52) and the methylated derivatives of both tautomeric forms indicate that the parent compound exists as a mixture containing comparable amounts of both forms in aqueous solution. Nuclear magnetic resonance spectra support this conclusion, but the ultraviolet spectra of the tautomeric compound and both alkylated derivatives are too similar to give information concerning the structural nature of the former. ... 

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. ... 

The predominance of structure 65 (R = H) in the equilibrium 65 66 has been reported on the basis of the ultraviolet spectral similarity of the potentially tautomeric compound and of 67. However, when R = COCH3, this hydroxy pyridine 1-imide reacts with diazomethane to yield 68, which has been interpreted to indicate that 66 is the predominant tautomer this conclusion is supported by the resultant changes in the pif values when the acetyl group is replaced by other acyl groups. 

The ultraviolet spectrum of the tautomeric compound 290 (R = H) 291 is qualitatively similar, but quantitatively dissimilar, from that of the methyl derivative (290, R Me), and it may be tentatively concluded that both forms 290 (R = H) and 291 are present... 

The X-ray studies of tautomeric compounds have demonstrated that several cases can be distinguished (Table VII) (94JHC695). 

Tautomeric compounds as guest included in a host (static or dynamic)... 

Gas-phase studies where relevant tautomeric compounds are described are ihore scarce, but include uracil, thymine, and adenine [97CPL(269)39]. In the case of the 2-pyridone/hydroxypyridine equilibrium, the intensity of the OH and NH stretching vibrations was measured for eight temperatures in the range from 428 to 533 K in the gas phase. This allows determination otAH and AS for the equilibrium (92JPC1562). 

Molecular design of tautomeric compounds Theoretical study of tautomerism of five-membered heterocycles (HMO)... 

Application of mass spectrometry for the analysis of tautomeric compounds... 

V. I. Minkin, L. P. Olekhnovich, and Y. A. Zhdanov, Molecular Design of Tautomeric Compounds, D. Reidel, Dordrecht, 1988. 

Design of Tautomeric Compounds, D. Reidel, Dordrecht/ Boston, 1988. 

Biquard and Grammaticakis demonstrated in 1941 that the ultraviolet spectra of 3-methyl- and 3,4-dimethyl-l-phenylpyrazol-5-one were intermediate between those of methylated derivatives of the CH (i.e., 55, R = R — Me) and NH forms (i.e., 56, R = Me, R — H or Me) of the compounds, concluding that the potentially tautomeric compounds exist as mixtures of these forms. However, they did not consider the possible occurrence of an OH form. Other ultraviolet... 

One of the most important applications of diazomethane depends on its ability to replace a mobile hydrogen atom by a methyl group. In comparison with other methylation agents, diazomethane occupies a rather special place this is, in part, because only rather strongly acidic protons are replaced. Because of the simple method of working up the reaction mixture, the reaction is especially well applicable for sensitive compounds and for small amounts. If tautomeric or potentially tautomeric compounds are treated with diazomethane, two... 

If these considerations and investigations are taken into account, the reaction scheme, Eqs. (5), (6), and (7), can be deduced for the methylation of tautomeric and potentially tautomeric compounds by diazomethane (itself a special case of a reaction of ambifunctional compounds with electrophilic reagents). A vital step in this scheme... 

The same starting compound 112 showed a totally different behavior when treated with trifluoroacetic acid (TFA), giving a rearrangement to 114 followed by spontaneous oxidation that afforded an equilibrium mixture of tautomeric compounds 115 and 116 (Scheme 15) <1999EJ03429>. 

Also, (5-phenyl-l,3,4-oxadiazol-2-yl)-7-hydroxycoumarin is a tautomeric compound. In dilute solutions it is almost totally present in its protonated nitrogen tautomeric form. The deprotonation is a reversible process (Scheme 2). Quantum-mechanical calculations were carried out and correlated with experimental observations <2000SAA1773>. 

Some reactions of tautomeric compounds 4a have already been discussed in Sections 5.06.5.2 and 5.06.6.1 because assignments of at least of some of these reactions to a particular section may be ambiguous. 

The following simple general formula expresses the important connexion which exists between the proportions of the tautomeric compounds at equilibrium and their solubilities in the solvent concerned (van t HofE, Dimroth) ... 

V.l. Minkin, L.P. Olekhnovich and Yu. A. Zhdanov Molecular Design of Tautomeric Compounds. 1988 ISBN 90-277-2478-4... 

In our discussion, we will divide tautomeric compounds according to the type of substituent involved, and under that heading consider all the various possibilities including structures of both neutral form and those for which only charge-separated forms can be written, and both pyridine and benzopyridine derivatives, and polysubstituted heterocycles. 

PE spectroscopy offers a method of investigating the tautomeric structure of pyridones and other related compounds in the gas phase by comparison of ionization potentials of the potentially tautomeric compound with those of fixed models. This method is discussed in CHEC 2.04. 

The tautomeric studies of azacytosines are not so complete as those of cytosine itself. The contribution of other tautomeric forms of azacytosines to the tautomeric equilibrium has not been evaluated (because of lack of model tautomeric compounds). It appears that 6-aza-substi-tution causes a tautomeric shift from form 3 of cytosine toward its imine form, 6. Thus, upon 6-aza-substitution the contribution of the imine tautomers to the tautomeric equilibrium of cytosine increases, while that of tautomers 3 decreases. 

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