In-solution tautomeric equilibria

Theoretical Consideration of In-Solution Tautomeric Equilibria in Relation to Drug Design... 

Many workers in recent years have been interested in the tautomeric equilibria pertaining to oxygenated imidazoles such as imidazolones, " " N-hydroxyimidazoles, and imidazole iV-oxides. The earlier results have been critically summarized. In the solid state l,2-dimethyl-5-phenylimidazol-4-one exists in the OH form, but insolubility prevented studies in solution. Theoretically l-methylimidazol-5-ones can exist in the forms 93-96 shown in Eq. (22). French workers ... 

Over the years, spectrophotometry (UV-VIS) has been used to study such physicochemical phenomena as heats of formation of molecular addition compounds and complexes in solution, determination of empirical formulas, formation constants of complexes in solution, hydration equilibria of carbonyl compounds, association constants of weak acids and bases in organic solvents, tautomeric equilibria involving acid base systems, protein-dye interactions, chlorophyll-protein complexes, vitamin A aldehyde-protein complex, association of cyanine-dyes, determination of reaction rates, determination of labile intermediates, and dissociation constants of acids and bases. 

Although aqueous solutions of D-xylose and o-glucose contain insignificant proportions of furanose forms, n.m.r. spectroscopy has indicated that 15% of the j8-furanoses are present in the tautomeric equilibria of the corresponding 3-0-methyl ethers these equilibria are not governed by stereochemical factors... 

These structural problems are also insoluble by physical methods alone. The infrared spectrum often gives an unambiguous decision about the structure in the solid state the characteristic bands of the carbonyl or the hydroxyl group decided whether the compound in question is a carbinolamine or an amino-aldehyde. However, tautomeric equilibria occur only in solution or in the liquid or gaseous states. Neither infrared nor ultraviolet spectroscopy are sufficiently sensitive to investigate equilibria in which the concentration of one of the isomers is very small but is still not negligible with respect to the chemical reaction. 

This technique provides quantitative information about tautomeric equilibria in the gas phase. The results are often complementary to those obtained by mass spectrometry (Section VII,E). In principle, gas-phase proton affinities, as determined by ICR, should provide quantitative data on tautomeric equilibria. The problem is the need to correct the measured values for the model compounds, generally methyl derivatives, by the so-called N-, 0-, or S-methylation effect. Since the difference in stability between tautomers is generally not too large (otherwise determination of the most stable tautomer is trivial) and since the methylation effects are difficult to calculate, the result is that proton affinity measurements allow only semi-quantitative estimates of individual tautomer stabilities. This is a problem similar to but more severe than that encountered in the method using solution basicities (76AHCS1, p. 20). 

Special attention has been given to the study of tautomeric equilibria in solutions of histidine 22 because the key functional role of such equilibria in proteins is recognized. In aqueous solutions the tautomers of histidine rapidly interconvert and only a single averaged signal is observed for each ring nitrogen (Scheme 10). 

By contrast, alkylamination of naphthazarin (7) in the presence of sodium dithionite followed by oxidation gives l,4-bis(alkylamino)-5,8-naphthoquinone (31).18,19 However, Kikuchi and co-workers20 obtained isomeric l,5-bis(alkylamino)-4,8-naphthoquinone (32) from the reaction of leuco naphthazarin (33) with alkylamine They also isolated 5-alkylamino-leuco-naphthazarin (34) as an intermediate, which is further aminated at the 1-position to give 32. Bloom and Dudek21 have studied the structure of leuco aminonaphthoquinones and their tautomeric equilibria in solution. They concluded that the reaction of leuco naphthazarin (33) or the leuco compound (35) derived from l,5-diamino-4,8-naphthoquinone (36) with methylamine gives mixtures of l,4-bis(methylamino)-31 (R = Me) and 1,5-bis(methylamino)naphthoquinones 32 (R = Me) after oxidation of leuco aminonaphthoquinones (Scheme 10). Some of the structures of leuco aminonaphthoquinones are shown in Scheme ll.20... 

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