Aromaticity and Tautomerism

Our previous treatment (76AHCS1, p. 12) contained a section called Chemical Methods to Study Tautomerism where the relationship between tautomerism and reactivity was discussed. Today, nobody uses chemical methods to study tautomerism. However, a great many reactions are carried out on tautomeric heterocycles, although few papers contain new insights on that topic. Authors desiring to explain reactivity results based on tautomerism must take great care to verify that the substrate is in the neutral form AH and not as a conjugated anion A or cation HAH, which are usually devoid of tautomerism. They must also realize that most frequently the reaction path from tautomers to products in- 

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The relationship between tautomerism and aromaticity is strong both in carbocyclic chemistry (e.g., phenol) [37, 38] and in heterocyclic chemistry (e.g., 2-hydroxypy-ridine) [39, 40], We consider that the cycle should be formed by covalent bonds, thus excluding the possibility that rings comprising hydrogen bonds, the so-called resonance assisted hydrogen bonds (RAHB), could be aromatic [41 45],... 

We have devoted two other papers to heteropentalenes, one to azapentalenes with one ring junction nitrogen atom (B series) and the other to azapentalenes with two ring junction nitrogen atoms (C series) (unpublished results from this group). In the first case we have focused our attention on tautomerism and aromaticity (energies and NICS). 

Conventions, and awareness of them by the user, are also required for metal bonds, tautomerism and aromaticity. These issues are too large to discuss here. 

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]. 

In this initial section the reactivities of the major types of azole aromatic rings are briefly considered in comparison with those which would be expected on the basis of electronic theory, and the reactions of these heteroaromatic systems are compared among themselves and with similar reactions of aliphatic and benzenoid compounds. Later in this chapter all the reactions are reconsidered in more detail. It is postulated that the reactions of azoles can only be rationalized and understood with reference to the complex tautomeric and acid-base equilibria shown by these systems. Tautomeric equilibria are discussed in Chapter 4.01. Acid-base equilibria are considered in Section 4.02.1.3 of the present chapter. 

After the publication of a book on the prototropic tautomerism of aromatic heterocycles (76AHC(Sl)l) which covered the literature up to 1975, the study of the tautomerism of pyrazoles has not made great strides. In this section the main conclusions of this earlier review will be summarized and comments on a few recent and significant references added. 

This 1,3-migration of hydrogen was also observed when 40 reacted with Lawesson s reagent to produce the dithiolactone 41. However, when y-hydroxy-a,P-unsaturated aldehyde 42 was reacted under similar conditions, thiophene 43 was prepared efficiently. These results are not surprising considering that the oxidation state of 42 is equivalent to the traditional saturated 1,4-dicarbonyl substrates of the Paal thiophene reaction via tautomerization of the double bond, and aromaticity is reestablished in the fully conjugated 43. 

Modern concepts have been extended to the chemistry of heterocyclic compounds more slowly than to the chemistry of aromatic and aliphatic systems, but efforts are now being made to classify and explain the properties and reactions of heterocyclic compounds in terms of these newer ideas (cf. reference 11). However, many of the most important heterocyclic compounds are potentially tautomeric, and elucidation of their tautomeric composition must precede a logical treatment of their properties. Further, many natural products such as the nucleic acids and alkaloids contain potentially tautomeric groups and information of this type is needed for a detailed explanation of th reactions which they undergo,... 

Several other review articles cover various aspects of tautomerism in six-membered heterocycles. Various aspects of prototropic tautomerism have been covered in a review article by Katritzky [91H(32)329] types of tautomerism, methods of study of aromatic tautomerism, and tautomeric equilibria in pyridines and other six-membered rings. Some generalizations have also been made. Another review article by Kurasawa, which appeared in two parts in 1995, covers, for the most part, the work of that author [95H(41)1805 95H(41)2057]. 

All the known porphyrin isomers are typical benzoid aromatic compounds which show distinctly porphyrin-like characteristic electronic absorption spectra.13 Also the complexation properties for metal ions, NH tautomerism and the NMR spectra are quite similar to the parent porphyrin structure. 

The so-called transdiazotizations are mechanistically related to the introduction of diazonio groups using sulfonic acid azides. An aromatic diazonium ion forms a triazene (diazoamino compound) with an aromatic amine the triazene tautomerizes and dissociates at the Na-Np bond of the original diazonium ion. This reaction is important for the synthesis of the 4-aminobiphenyl-4,-diazonium ion, which cannot be obtained by direct (mono-)diazotization of 4,4 -diaminobiphenyl (Allan and... 

In azo couplings with carbonyl compounds, three tautomeric products are possible, compared with only two for phenols and aromatic amines (discussed in Section 12.1). The ketohydrazone 12.75 is most often dominant, but for easily enolizable 1,3-dicarbonyl compounds (X=CO-R and similar structures) the azoenol 12.76 is the major product. The azoketone 12.77 is often postulated as primary product, but has rarely been identified in an unambiguous fashion using modern methods. The CH2 group should be easily detectable in the lH NMR spectrum. 

Nor can there be any question of real tautomerism in the case of phenol. In its chemical properties phenol resembles the aliphatic enols in all respects. We need only recall the agreement in the acid character, the production of colour with ferric chloride, and the reactions with halogens, nitrous acid, and aromatic diazo-compounds (coupling), caused by the activity of the double bond and proceeding in the same way in phenols and aliphatic enols. The enol nature of phenol provides valuable support for the conception of the constitution of benzene as expressed in the Kekule-Thiele formula, since it is an expression of the tendency of the ring to maintain the aromatic state of lowest energy. In this connexion the hypothetical keto-form of phenol (A)—not yet obtained—would be of interest in comparison with... 

Burkhardt, "Arthur Lapworth and Others," 143. C. K. Ingold, "The Significance of Tautomerism and of the Reactions of Aromatic Compounds in the Electronic Theory of Organic Reactions," JCS (1933) 1120 and C. 

While at Leeds from 1924 to 1930, Ingold s laboratory focused on three main topics of research (1) the nature and mechanism of orienting effects of groups in aromatic substitution (mainly nitration) (2) the study of prototropic rearrangements (shifts of H+) and aniontropic rearrangements (shifts of anions) as the ionic mechanisms of tautomerism and (3) the effect of polar substituents on the velocity and orientation of addition reactions to unsaturated systems. One of Ingold s students at Leeds, John William Baker, wrote a widely read book on tautomerism. 16... 

The beauty of the Dewar structure, Ingold remarked, lay in the fact that it explains quinoid transformations and aromatic tautomerism as well-established principles of aliphatic and alicyclic chemistry, that is, it provided a rationale for the unification of aliphatic and aromatic chemistry. 

Busy with the move from Leeds to London in 1930, Ingold afterward was in residence at Stanford University in California in 1932, with some leisure to work out generalizations of the results already at hand. He soon published two widely read pieces "Significance of Tautomerism and of the Reactions of Aromatic Compounds in the Electronic Theory of Organic Reactions," in the Journal of the Chemical Society, and the essay review, "Principles of an Electronic Theory of Organic Reactions," in Chemical Reviews.58... 

The concept of aromaticity has been linked to those of tautomerism and equilibrium by using KT, or an equilibrium constant as a measure of the binding energy difference between the pyridinoid and pyridonoid forms, and comparing this to the corresponding quantities for saturated derivatives (Scheme 12). 

The reaction of azides with ethoxyacetylene (98) has been studied by Italian authors. With aliphatic and aromatic azides, the expected 1-substituted 5-ethoxy-l,2,3-triazoles (99) are obtained.310-311 Sulfonyl azides, on the other hand, react with ethoxyacetylene at room temperature to yield no triazoles but the valence tautomeric diazo compounds (100).312-313... 

Tautomerism and the Aromatic Stabilization of Heterocyclic Compounds A. R. Katritzky, Uniw. Adama Mickiewicza Poznaniu, Wydz. Mat., Fiz. Chem., Ser. Chem., 1975, 18, 129-131. 

Unsubstituted hydrazones of aromatic ketones and aldehydes have been converted in high yield to alkyl chlorides under Swern oxidation conditions, although the substrate actually undergoes a net reduction.93 When the hydrazone is dideuterated, a deuterium ends up on the carbon, supporting the proposed intermediacy of cation (34), which tautomerizes and loses N2, to give a carbocation which combines with the chloride. 

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