Quinone Tautomerism

Despite the importance of the oxidative polymerization of 5,6-dihydroxyin-dole, in the biosynthesis of pigments, little experimental data are known on the oxidation chemistry of the oligomers of 1. For such reasons, three major dimers of 1, such as 2-4 (Scheme 2.9), have been computationally investigated at PBEO/ 6-31+G(d,p) level of theory both in gas and in aqueous solution (by PCM solvation model) to clarify the quinone methide/o-quinone tautomeric distribution. 

Enol imine-enaminone and phenol—quinone tautomerism in (arylazo) naphthols and in analogous Schiff bases were studied by Fabian et al. [92, 93]. In all these molecules there is a favorable N- -H- -O intramolecular hydrogen bond. Depending on the X-H sigma bond (X = N, O), there are two possible tautomers in solution. The solvent effect was calculated on the equilibrium [92], and a combined effect of the solvent and the benzene substituent was studied in [93]. While the FEP/MC simulations provided consistent organic solvent effects in accord with the experimental results [92], the wide spectrum of the solvent-effect calculation methods could predict rather diverse results for several groups of systems in [93]. 

A tautomeric equilibrium between quinone and quinone methide tautomers has been proposed to exist for the compounds which are obtained by oxidation of 5,6-dihydroxy indole (Scheme 18) (92TL3045). 

Coelenterazine (A) is oxidized into dehydrocoelenterazine (D) by MnC>2 in a mixed solvent of ethanol and ether (Inoue et al., 1977b). Dehydrocoelenterazine (C26H19O3N3) can be obtained as dark red crystals. It does not have the capability of chemiluminescence. The ultraviolet absorption spectrum (Fig. 5.6) shows its absorption maxima at 425 nm (e 24,400) and 536 nm (g 12,600) in ethanol. An addition of NaOH significantly increases the 536 nm peak at the expense of the 425 nm peak. Dehydrocoelenterazine can take a tautomeric structure of quinone type (not shown), in which the phenolic proton on the 2-substituent is shifted onto the N(7) of the imida-zopyrazinone ring. Dehydrocoelenterazine can be readily reduced to... 

These DFT data provide a consistent picture for the tautomerization equilibria involving the dimers 2-4, which highlight the extended quinone methides 2a, 3a, and 4a as the most stable tautomers for all biindolyl quinones investigated. 

The tautomeric product distribution has been a prerequisite for a further investigation aimed at predicting absorption properties of the transient semiquinones and quinones generated by pulse radiolytic oxidation of 2-4. The simulation of electronic absorption spectra has been computed using the TD-DFTapproach both in vacuum and in aqueous solution, using the large 6-311 + +G(2d,2p) basis set.19... 

The process that affords the alkenes with13 C = 45 ppm is essentially an internal redox reaction wherein electrons flow from the fused tetrahydropyrido ring to the quinone ring by means of a series of tautomerizations. 

The results of AE calculations shown in Scheme 7.26 show that internal hydrogen bonds can influence the thermodynamics of quinone methide tautomerization in some instances. For the prekinamycin quinone methide without internal hydrogen bonds... 

Table 7.3 shows the concentrations of 1-5 that result in 50% growth inhibition (GI50) of five human cancer cell lines. Inspection of these data reveals that cytostatic activity of 1 and 3-5 depends on the thermodynamic favorability of the quinone methide species compared to the corresponding keto form. The most cytostatic prekinamycins 1 and 5 are associated with the thermodynamically stable quinone methides. In contrast, the inactive prekinamycins 3 and 4 are associated with thermodynamically stable keto tautomers. The exception is prekinamycin 2, which is cytostatic and possesses a relatively stable keto tautomer 3 compared to its quinone methide. Although the AE value for quinone methide tautomerization can predict cytostatic properties, prekinamycin 2 shows that there must be other factors determining biological activity. 

Most coenzymes have aromatic heterocycles as major constituents. While enzymes possess purely protein structures, coenzymes incorporate non-amino acid moieties, most of them aromatic nitrogen het-erocycles. Coenzymes are essential for the redox biochemical transformations, e.g., nicotinamide adenine dinucleotide (NAD, 13) and flavin adenine dinucleotide (FAD, 14) (Scheme 5). Both are hydrogen transporters through their tautomeric forms that allow hydrogen uptake at the termini of the quinon-oid chain. Thiamine pyrophosphate (15) is a coenzyme that assists the decarboxylation of pyruvic acid, a very important biologic reaction (Scheme 6). 

On various grounds, however, this explanation may be questioned. In particular it may be pointed out that m-nitrophenol behaves like the other two isomers and hence its alkali salts must also be quinonoid in form. But wi-quinones are unknown throughout the whole range of the aromatic compounds. Moreover, there are numerous examples of substances which undergo a deepening in colour when they form salts but cannot change to a tautomeric quinone. Thus the disodium and dipotassium salts of yellowish-brown anthraquinol are deep blood-red in colour (p. 335). 

Tautomerism exists in the case of o- and p-nitrosophenols and naphthols which exist mainly as the quinone oximes, and which also give high field shifts. The values for the oxime groups in the 1,2-naphthoquinones, for example, were 229 and 265 ppm for the 1-oxime and the 2-oxime respectively. 

The solid-solid transformation of 2-amino-3-hydroxy-6-phenylazopyridine, 57a, to 57b proceeds through two intermediate phases (119). X-Ray and IR studies of the former, low-temperature, and the latter, high-temperature phase show that they are the phenolazo and quinone hydrazone forms, respectively. This solid-state tautomerism can be accounted for by a cooperative intermolecular shift of protons across the various hydrogen bonds. However, because of the complexity of the hydrogen-bond network, the actual pathway of the proton shift has not been uniquely defined. 

The mixture of quinone methides initially formed by combination of the coniferyl radicals in their various mcsomeric forms, i.e. (I), (III), (V), (IX) and others, can be detected by means of their characteristic spectrum with a maximum at about 312 mp (52) the haU-hfe of the mixture in 70 % aqueous dioxan is 1 hour. Those quinone methides that can rearomatize by keto-enol tautomerism, e.g. (IX), or intramolecular additions, e.g. (I) or (III) may become stabilized faster than those of type (V) which rely on addition of a foreign molecule. The quinone methides that rearomatize intramolecularly appear to react exclusively in this way, probably by a concerted mechanism that represents collapse of the activated transition state. 

The valence tautomerism of cobalt-quinone complexes in non-aqueous solvents... 

Various nitrosoarenes have been utilized as benzofurazan precursors including o-azido derivatives generated from the o-chloro analogues <66JCS(B)1004>, and 1-amino-2-nitrosoarenes which can be oxidized with ferricyanide or hypochlorite. Treatment of o-nitrosophenols with hydroxylamine also affords the furazan, presumably via an oximation-dehydration pathway involving the tautomeric o-quinone monooxime. Other related approaches involve the reduction of o-dinitroarenes with borohydride, and the thermolysis of o-nitroanilines and o-nitroacetanilides. 

The principal methods for forming the heterocyclic ring of benzofuroxans involve oxidation of o-quinone dioximes, thermolysis of o-nitroaryl azides, and oxidation of o-nitroanilines (Scheme 25). Ring chain tautomerism (Section 4.05.5.2.1) for the A -oxides of asymmetrically substituted benzofuroxans is more facile than for monocyclic analogues and mixtures of isomers may result. Benzofuroxans are also formed by Boulton-Katritzky rearrangement of 7-nitro-2,l-benzisoxazoles and 4(7)-nitrobenzofuroxans (Section 4.05.5.2.5). 

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