8-Hydroxyquinolines, tautomers

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). 

Although hydroxyquinolines in which the hydroxy substituent is present in the benzene ring are known and show phenolic activity, 2- and 4-hydroxyquinoline exist solely as the quinolone tautomers (Box 3.2). 

The chemistry used to prepare the antischistosomal hydroxyquinolines provided the initial entry to this series. Thus, addition-elimination of aminopicoline (38-1) to EMME (38-2) gives the corresponding enamino ester (38-3). Thermal cyclization of that intermediate leads to the hydroxyquinoline (38-4). Reaction of the ambident anion from that compound leads to alkylation via the keto tautomer and thus the formation of the Al-alkylated derivative (38-5). Saponification of the ester then gives nalidixic acid (38-6) [44]. It has incidentally been shown that the presence of the strong Michael acceptor function in this series plays a little role in the mechanism of action in these compounds. 

Such compounds are treated as hydroxyl compounds even if their dominant tautomeric form is the keto tautomer. Reduction usually takes place either in the nucleus or at the carbonyl group. Simple examples of the first type are maleic imide [393, 394] and hydra-zide [395] in many other examples a second reduction leads to a ring contraction. Reduction of the keto group leads to a hydroxyl group in many cases water is eliminated and a further reduction takes place. An example of this is the reduction of AT-methylsuc-cinimide to AT-methylpyrrolidone [396]. Oxidation of hydroxy-substituted dihydrohetero-cycles may introduce a double bond an example is the oxidation of 1,2-dihydro-3-methoxycarbonyl-4-hydroxyquinoline in AcOH/7-BuOH to 1,4-dihydro-4-oxo-3-methox-ycarbonylquinoline [397]. The use of pyrrolidone as a probase is discussed in Chapter 30 [398]. 

The double proton-transfer reactions of 7-hydroxyquinoline with water at both gates of cyclodextrins have been studied (98CPL(296)335). It was shown that whereas in neutral water both tautomers coexist (85% of 31a and 15% of 31b Kj — 5.7 +1), addition of /1-cyclodextrin results in their conversion into the encapsulated hydroxy tautomer thus shifting the tautomeric equilibrium entirely to 31a. 

Few hydroxythienopyridines have been described. A major point of interest is the extent to which the compounds exist as the hydroxy or keto tautomer. Derivatives in which the group is attached to the pyridine ring would be expected to resemble their quinoline or isoquinoline analogs, but, in view of the fact that hydroxythiophenes exist to some extent in keto forms, the genuinely phenolic properties of hydroxy groups on the benzene rings of the isosteric systems might not be reproduced in thienopyridines. 1-Hydroxyisoquinoline and 2- and 4-hydroxy-quinoline exist almost exclusively in the keto forms, whereas 3-hydroxyquinoline and 4-hydroxyisoquinoline are extensively enolized in 3-hydroxyisoquinoline the two forms are of comparable stability and which one predominates is dependent on the solvent. A similar pattern is... 

Here we present CNIK)/2 calculations of three classes of compounds 4-quinolones, 4-chromones, and 1,4-naphthoquinones that are all inhibitors of PS II. We compared quinolones with the tautomeric hydroxyquinolines, the latter form likely to be the form bound to the membrane as already discussed. The tautomers do not differ significantly, hence we used for symmetry reasons the quinolone form in the comparison with the chromones and naphthoquinones... 

Experimental (NMR, X-ray and DSC) and theoretical studies [DFT B3LYP/6-311 + + G (d,p)] by Nieto et al. have permitted to establish the structure of the main tautomeric form of 8-hydroxycarbostyril. " In the gas phase two tautomers, 8-hydroxyquinolin-2(lH)-one and 2,8-quinolinediol show similar stabilities. In solid state two polymorphs of 8-hydro-xyquinolin-2(lH)-one have been isolated and their structures elucidated polymorph A, which crystallizes in orthorhombic space group, and polymorph B, which crystallizes in monoclinic space group. The arrangement of molecules in both structures is characterized by intermolecular N-H... O and 0-H... 0 hydrogen bonds. 

Hydroxyquinoline carboxylic acids and their conjugate acids and bases were characterized by C and N NMR spectroscopy in solution and in the solid-state. It was found that differences in C and, in particular, N chemical shift patterns allow to distinguish between individual tautomers and confirm the presence of zwitterionic species in the solid-state. Solution NMR spectra in DMSO-Jg showed effects resulting as a consequence of dynamic exchange and suggest the presence of an equilibrium mixture of hydroxyquinoline carboxylic acid and zwitterionic hydroxyquinolinium carboxylate tautomers. 

The structures shown in Figure 12.16 are based on 4-hydroxyquinoline as tautomeric backbone [80], which as stated by Sherin et al. exists in gas phase, water, and DMSO [81] as keto tautomer. In spite of limited experimental data. 

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