7- Hydroxyquinoline, tautomerism

Hydroxyquinolines (Quinolinols). A number of methods have been employed for their preparation. A modified Chichibabia reaction of quinoline ia fused KOH—NaOH at 240°C produces 70% of 2-hydroxyquiQoline [59-31-4] (121). Alternative names based on the facile keto—enol tautomerism of two of these compounds are 2(1H) and 4(lJd)-quiQolinone none of the other quinolinols show this property. The treatment of... 

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). 

Cyclocondensation of 8-hydroxyquinolin-2(l//)-one and chloroacetone in the presence of K2CO3 in dry DMF at ambient temperature for 24 h afforded 2,3-dihydro-3-hydroxy-3-methyl-5//-pyrido[l,2,3- /e]-l,4-benzoxa-zin-5-one (240, R = Me) (97HCA1161). A tautomeric mixture of ring-opened... 

The synthesis of this aminoquinoline starts with one of the standard sequences for preparation of 4-hydroxyquinolines, i.e., with the formation of the Shiff base (5) from the appropriately substituted aniline and diethyl oxaloacetate. Thermal cycliza-tion gives the quinolone (6) this then spontaneously tautomerizes to the enol form (7). Saponification followed by decarboxylation gives the desired quinolol... 

Bardez E, Devol I, Larrey B et al (1997) Excited-state processes in 8-hydroxyquinoline photoinduced tautomerization and solvation effects. J Phys Chem B 101 7786-7793... 

We have demonstrated that the novel antitumor agent 10-hydroxycamptothecin has remarkable excited-state acidity. In contrast to simple 6-hydroxyquinoline, no tautomerization is observed. The implications for the use of proton transfer dynamics in studying the microenvironment of cells remains to be demonstrated. 

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]. 

Primary deuterium isotope effects have also been measured in 8-hydroxyquinoline N-oxides (32) . It was found that a plot of A( H, H) vs. 50H had a different slope than observed for tautomeric hydroxyquinones and /3-diketones . 

Very favourable hydrogen bonding may occur in substituted 8-hydroxyquinoline N-oxides (substituted 32) judging from the 50H value (in the 5,7-dinitro-8-quinolinol N-oxide a value of 20.38 ppm is found) as well as the deuterium isotope effects on the C chemical shifts. Complicated substituent effects are found, because substiments such as bromine may interact with both the OH and the N—O group. No tautomerism was observed... 

Shchavlev, A.E., Pankratov, A.N., and Shalabay, A.V., DFT computational studies on rotation barriers, tautomerism, intramolecular hydrogen bond and solvent effects in 8-hydroxyquinoline, Int. J. Quantum Chem., 106, 876-886 (2006). 

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. 

Hydroxypyridine (201) itself possesses latent 1,3-dipolar character because of tautomerism involving 1-protiopyridinium 3-oxide (202). Aprotic diazotization of anthranilic acid in the presence of 201 gives two heterocyclic products [196 (20%) and 203 (23%)] which were isolated in separate experiments run under almost identical conditions.103,105 Formation of the bis-adduct 196 must involve cycloaddition of benzyne to 202 and N-phenylation and there is some evidence from related additions to 2//-phthalazin-1 -one (208) that the steps occur in this order.3 7b Formation of the isocoumarin structure 203 apparently involves electrophilic substitution of 201 by the benzyne precursor 5, followed by lactonization. From 3-hydroxy-6-methylpyridine compounds analogous to 196 and 203 were also obtained (10 and 29%, respectively). 3-Hydroxyquinoline afforded only the corresponding isocoumarin 204 (20%) whereas 4-hydroxyisoquinoline gave 4-phenoxyisoquinoline (12%) and the bis-adduct 205 (12%) with benzyne.103,105... 

This is substantiated by charge distributions of hydroxyquinolines and of the tautomeric quinolones obtained from quantum mechanical calculations. It shows a negative n-charge at a particular essential atom. 

In the literature there are controversial arguments concerning the structure of the quinolones, whether or not they exist in the tautomeric form as 4-hydroxyquinolines. Careful C-NMR spectroscopy of some 2-CF3 substituted compounds has revealed that they actually exist (in diluted CHCl -solution) as 4-hydroxyquinolines. Therefore we carried out CNDO/2 calculations on 2-CF3-3-Cl-4-quinolone and the corresponding hydroxyquinoline (Table IX). 

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... 

Scheme 21 Tautomeric equilibria and pharmaceutical names of 8-hydroxyquinoline derivatives.

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. 

Attempts have been made to deduce the structure of the predominant form of a potentially tautomeric compound from the shifts which occur in the ultraviolet spectrum of the compound in question on passing from neutral to basic or acidic solutions. The fact that no bathochromic shifts were observed for 2- and 4-hydroxyquinoline and 1-hydroxyisoquinoline under these conditions was taken as evidence that they existed in the oxo forrn [similar work on substituted quinol-4-ones led to no definite conclusions ]. A knowledge of the dissociation constants is essential to studies of this type, and the conclusions can, in any case, be only very tentative. A further dif-... 

The coexistence of the NH-quinolin-4(lH)-one and 4-hydroxyquinoline isomers has been confirmed by spectrometric analysis. However, the exclusive NH-4-OXO nature of these alkaloids in solution phase (NMR) and solid state (IR and X-ray) has also been corroborated (213). For example, galipoline, isolated from Angostura trifoliate (Rutaceae) (Table VI), has the potential to exist in tautomeric equilibrium (Scheme 14), explaining a number of reports which have appeared showing the structure of galipoline (1,214), either as 2-(3, 4-dimethoxyphenylethyl)-4-hydroxyquinoline or as 2-(3,4-dimethoxyphenvlethvl)-quinolin-4(lH)-one (40). 

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