CH tautomers

In the solid state the CH tautomer (78a) is always readily identified, but the OH and NH tautomers (that, in some cases, coexist in the crystal (73CSC469)) are difficult to differentiate due to the strong hydrogen bonds that shift the u(CO) band to the region of pyrazole vibrations. This source of complications is not present in the fixed forms that can always be identified by their IR spectra, both in solution and in the solid state. 

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). 

The predominance in the gas phase of the CH tautomers in the case of several pyrazolinones including one 3-aminopyrazolin-5-one was demonstrated by PES [88JCS(P2)641] this result is consistent with previous findings (76AHCS1, p. 325). The same technique was applied to the study of the amino/imino equilibrium in 9-amino and 9-(methylamino)acridines [91MI(61)166] although both tautomers have similar stabilities, the experimental data are in better agreement with the amino tautomer. 

Absolute predominance of nonaromatic CH tautomers is also the situation for benzothiazepinones 52 (88BSB387, 89BSB405, 97JHC953) and pyrazolodiazepinones 53 (77JMC1562). 

Of the four fundamental pyrazolopyrimidine systems two (1, 2) do not display tautomerism. The [3,4-d]-system exists as four NH-tautomers (3-6), and CH-tautomers can also be written (e.g., 7). We will normally write the [3,4-d]-system as in structure 3. The [4,3-d]-system possesses two uncharged (8, 9) and three zwitterionic NH- (e.g., 10) and CH-forms (e.g., 11). We will normally write this system as 8. 

When both rings in azapentalenes have more than one nitrogen atom, the CH tautomer is unstable thus structure 27Sa, proposed by some workers,148 is unlikely, and the compound is better represented by the NH forms 275b or 275c. The factors that influence the relative stabilities of NH tautomers are more complex and can be summarized in four rules ... 

Fig. 4.13. illustrates how to apply carbon-13 NMR for analysis of tautomerism in heterocyclic chemistry 3-Methyl-5-oxo-l-phenyl-4,5-dihydropyrazole (the Knorr-pyrazolone ) is shown to exist as the CH tautomer B with a CH2 carbon at 43.1 ppm in chloroform solution (Fig. 4.13(a)), while the OH tautomer A predominates (90%) in hexadeuteriodimethyl sulfoxide (Fig. 4.13(b) [73 i]. 

The non-aromatic CH tautomers of pyrazolones have a malonic-like reactivity due to the fact that the hydrogen atoms of the CH2 group at position 4 are acidic because the conjugate anion (239) is fully delocalized. Figure 27 illustrates some classical reactions of 3-methyl-l-phenyl-2-pyrazolin-5-one (396) (64HC(20)l). 

There are various forms of tautomerism which operate in the different purine species. (1) Prototropy which involves attachment of the proton to any one of the four ring nitrogen atoms (Scheme 5). Corresponding CH tautomers, for example (52), seem to be of little significance. (2) Amine-imine tautomerism which operates in the aminopurines such as adenine (Scheme 6). (3) Lactam-lactim tautomerism as in the hydroxypurines such as hypoxanthine (Scheme 7) and the related thioxo-thiol tautomerism (53) and (54) in the biologically imporfant mercaptopurines (Scheme 8). The subject has recently been discussed in some detail <76AHC(Si)502>. 

In fact, very large basis set, correlated calculations suggest that the CH tautomer is favored over the NH in the gas phase by only 6.2 kcal/mol. Assuming an approximately equal mixture of the two tautomers in aqueous solution,3i3 the AMI-SMIa model is within about 1 kcal/mol of correctly predicting the relative free energies of solvation. The more general AM1-SM2 model is not quite as accurate in its consideration of heteroatom-bound protons, and it thus provides a somewhat poorer prediction in this instance, although it remains closer than any of the other models. 

Purine can form four NH tautomeric forms depending on the site of attachment of the proton at the ring nitrogens (A-D). The CH tautomers are of minor importance. Different tautomeric forms can be observed in the gas phase, in solution, or in the solid slate. According to quantum mechanical calculations, the H- and the 3/T-taulomers A and B are much less stable than the IH- and the 9//-tautomers C and D, respectively. Only the latter are detected in solution. 

The 4-CH tautomer (C) is clearly nonaromatic, whereas for the 2(6)-NH form (A) aromatic resonance forms can be written. 

In 3,5-dioxo derivatives, the 4-CH tautomer is preferred in all cases (86MRC444), Of the possible tautomeric equilibria keto enol and lactam lactim, in no cases has the enol form been observed. However, the presence of the lactim form has been detected by C-NMR spectroscopy (86TH1) (Section II,A,3,b). 

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