Annular ring tautomerism

There has been much interest in the study of the prototropic tautomeric equilibria of heterocyclic compounds since tautomerism influences their chemical/biological properties. The phenomenon of tautomerism is related to such important questions as aromaticity and lone pair-lone pair repulsions. Experimental studies in tautomerism are still a challenge to the theoretical studies. 

Indazoles can also show tautomeric forms. MP2-6-31G calculations on H- and 277-indazole annular tautomers showed that the 1/7-tautomer 86 is more stable the 2/7-tautomer 87 by 3.6kcalmoP 1996J(P2)57 . This result was further confirmed by the fact that the microwave rotational constants were reproduced with great accuracy. Also, electronic spectra recorded at 80 °C provided experimental evidence for the clear predominance of 177-indazole in the gas phase. The relative stabilities, PAs, and dipole moments for the tautomeric forms of some 3-substituted indazoles were calculated with full geometry optimization using AMI, PM3, and MNDO methods in the gas phase 2002JMT(583)137 . When the annular tautomerism is taken into account, the results of the semi-empirical AMI, PM3, and MNDO calculations confirmed that the 1/7-form 88 of the studied molecules is more stable than the 2/7-form 89 as stated in the previous literature. 

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The 1,2,5-oxadiazole ring is a stable system and annular-group tautomerism is not favored. Although three tautomeric forms can be drawn for 3-hydroxyfurazans (Scheme 3) IR and NMR data for chloroform solutions show only the presence of the hydroxy compound. Ring-chain tautomerism is an important feature of furoxan chemistry and the equilibration between the isomeric furoxans is discussed in detail later in this chapter (Section 4.05.5.2.1). 

Annular tautomerism (e.g. 133 134) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (133 R = H) and pyrazole (135 R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. Flowever, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (136) than in (137), and UV spectral comparisons show that benzotriazole exists predominantly as (136). 

A variety of 2H- (121, X = O) and 4H- (122, X = O) 1,3,5-oxadiazines has been studied and eharaeterized, whereas 2//-l,3,5-thiadiazines 121 (X = S), unlike the 4H isomers 122 (X = S), are uneommon. The most eommon type of tautomerie intereonversions for sueh systems is ring-ehain tautomerism. A few studies on substituent tautomerism have also been earried out however, no data on annular tautomerism have yet appeared in the literature. 

The volume ends with a chapter by B. Stanovnik and M. Tisler of the University of Ljubljana, Slovenia, and A. R. Katritzky and O. V. Denisko of the University of Plorida on the annular tautomerism of six-membered ring heterocycles. This represents a further installment in our comprehensive update of heteroaromatic tautomerism, which was the subject of several chapters in Volumes 79 and 80 of this series. 

Only two isomeric pyrazolopyrazines are possible 1/f-pyrazolo [3,4- >]pyrazine (59) and pyrazolo[l,5-a]pyrazine (60). Derivatives of both ring systems are known. Annular tautomerism could occur in 59 [cf. 4 f-pyrazolo[3,4-( ]pyrazine (59a) ]. 

Structure of Five-membered Rings with Two or More Heteroatoms Table 42 Annular Tautomerism of Azoles ... 

There are two important types of tautomerism found for small and large rings valence bond tautomerism and (to a somewhat lesser extent) annular prototropy. 

Boiling points and melting points are considered from the point of view of intermolecular forces between the molecules, together with solubilities and chromatographic behavior, both gas and liquid chromatography. The topic of aromaticity and stability in general is covered as befits its importance. Conformations, particularly of the cyclic non-planar compounds, are dealt with. A section on tautomerism covers both prototropic tautomerism (annular and of substituents) and ring-chain tautomerism. 

Unsymmetrical /i-dikctoncs can form two /i-kcto—cnol tautomers, (90a), (90b). The corresponding N//-pyrazolcs—readily synthesized from the diketones—exhibit annular tautomerism, (91a), (91b). These tautomerisms have been probed via AMI semiempirical calculations that show that the two phenomena are related 135 in each case the position of equilibrium is strongly influenced by whether or not the CC double bond is part of (another) ring system (the Mills-Nixon effect). 

Obviously the annular tautomerism of, for instance pyrazoles, and the resonance forms of 1,2-dihydrocyclobutabenzene are fundamentally different, but one can assume that the experimentally measurable equilibrium constant in 48 will reflect the Mills-Nixon effect [62-65], Calculations show that the effect should be very considerable with small rings (cyclobutane, 48, cyclopropane, 42) that are difficult to synthesize. However, we have succeeded in preparing compound 49 that exists as 49a, as predicted by the Mills-Nixon effect [65],... 

Annular tautomers are prototropic tautomers in which the migrating proton is restricted to ring atoms. For these five-membered heterocycles, annular tautomerism can only occur with pyrrole 2 and its polycyclic derivatives. There is no authenticated case of the monocyclic pyrrolenine tautomeric forms 211 and 212 predominating, presumably due to the required loss of resonance energy in these nonaromatic tautomers . 

Systematic replacement of CH in pyrrole 1 (Chapter 2.3) by N leads to nine additional monocyclic heteroaromatic nitrogen systems 2-10 (Figure 1), which are known collectively as azoles. Annular tautomerism is an important feature of all azoles having an NH function. For example, the triazoles 4 and 6, the triazoles 5 and 7, and the tetrazoles 8 and 9 can equilibrate by proton transfer (see Section 2.4.5). N-Substituted derivatives cannot equilibrate. Tautomers of the parent ring systems of all the azoles except pentazole 10 are known TV-aryl derivatives of pentazole have been characterized . 

Six-six condensed heterocyclic systems without a tautomeric functional group(s) [for instance, pteridine 135 (R = R2 = R4 = H)], do not exhibit prototropic tautomerism. The introduction of an oxo(thioxo)- and/or amino group(s) into the pteridine system, and the appearance of at least one NH group in the ring, leads to functional and/or annular tautomerism. Pteridine is formally the parent of three groups of compounds of particular interest because of their biological importance pterins (136), lumazines (137), and flavins (138). 

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