Hydroxy-, derivatives mercapto-, tautomerism

Hydroxy and mercapto substituents at the 3- and 5-positions can also exist in tautomeric forms (see Section 4.01.5.2) and can be alkylated at either the substituent or the ring nitrogen atom. 3-Methoxy groups are not replaced by nucleophiles, but both 3- and 5-alkylthio groups react readily, as does 3-methoxy-l,2-benzisothiazole. Alkylthio compounds can be oxidized to sulfoxides and sulfones, and the latter readily undergo nucleophilic replacement. All the hydroxy compounds react with phosphorus pentachloride to give the chloro derivatives. 

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

The nature and position of the cyclic heteroatoms within the five-membered rings of azoles can affect the positions of the prototropic tautomeric eqihbria, particularly of hydroxy and mercapto derivatives. 

A strictly dehned region of chemical shifts of C2, C4, and C5 atoms in A-oxides of 4A-imidazoles allows to dehne clearly the position of the A-oxide oxygen atom (102). Chemical shifts of the a-C nitrone group in a-N-, O-, and S-substituted nitrones are located in the region of 137 to 150 ppm (388, 413). On the basis of 13C NMR analysis of 3-imidazoline-3-oxide derivatives, the position of tautomeric equilibria in amino-, hydroxy-, and mercapto- nitrones has been estimated. It is shown that tautomeric equilibria in OH- and SH-derivatives are shifted toward the oxo and thioxo forms (approximately 95%), while amino derivatives remain as amino nitrones (413). In the compounds with an intracyclic amino group, an aminonitrone (A) - A-hydroxyaminoimino (B) tautomeric equilibrium was observed (Scheme 2.76), depending on both, the nature of the solvent and the character of the substituent in position 2 of the heterocycle (414). 

Thiono-mercapto and amino-imino tautomerism of azines. In the same heterocyclic systems, the stability of thiols with respect to the corresponding thione form is considerably higher than hydroxy derivatives with respect to their oxo forms. In the gas phase 2- and 4-mercaptopyridine are the major tautomers, e.g., 191. 15N NMR spectroscopy is useful for estimating the tautomeric composition of mercaptopyridines in solution. 2-Mercaptopyr-idine in acetone or methanol and 4-mercaptopyridine 191 in methanol or acetone/DMSO were estimated to be ca. 95% in the thione form, e.g., 192. This solvent effect can be attributed to the polarity of the thione tautomers <2006AHC(91)1>. 

Aminoimidazoles might be expected to prove more complicated than the analogous hydroxy and mercapto derivatives because of the possibility that an R group on NHR could have a marked effect on the position of tautomeric equilibrium, particularly if R is an acyl or sulfonyl function. However, amines are much weaker acids than hydroxy or mercapto compounds and so it should not be necessary to consider zwitterionic structures to any extent an NH group is not at all likely. 

The Structures and Reactions of Hydroxy- and Mercapto-thiophens and their Simple Derivatives.—2-Hydroxythiophens can in principle exist in three tautomeric forms, the hydroxy-form (110) and the 3- (111) and 4-thiolen-2-one (111a) forms. During recent years a series of derivatives of the 2-hydroxythiophen system, substituted with halogen, methoxy, aryl, and... 

The Structure and Reactions of Hydroxy- and Mercapto-thio ais.—Some tautomeric 2,5-dialkyl-3-hydroxythiophen systems have been prepared and characterized as acetoxy-derivatives. The equilibration between the two tautomeric forms of these systems is very rapid and the influence of substituents and solvent on the equilibrium has been determined.2,5-Di-formyl-3-hydroxythiophen has been synthesized by dealkylation of the t-butoxy-derivative and exists exclusively in the hydroxy form. The product distribution in the alkylation of the thallium salt of the... 

Table 11 summarizes the main results on the tautomerism of mono-hydroxy-, -mercapto-, -amino- and -methyl-azines and their benzo derivatives, in water. At first sight the equilibrium between 2-hydroxypyridine (71) and pyridin-2-one (72) is one between a benzenoid and a non-benzenoid molecule respectively (71a 72a). However, the pyridinone evidently... 

Table 11 summarizes the main results on the tautomerism of mono-hydroxy-, -mercapto-, -amino- and -methyl-azines and their benzo derivatives, in water. At first sight the equilibrium between 2-hydroxypyridine (71) and pyridin-2-one (72) is one between a benzenoid and a non-benzenoid molecule respectively (71a 72a). However, the pyridinone evidently has a continuous cyclic p- orbital system, containing six it- electrons, the usual aromatic count, if the carbonyl group contributes none. This assumption implies the formula (72b), from which by redistribution of electrons we arrive at (72c), which has the same benzenoid system as (71a). Further canonical forms (71b, 71c) can be drawn of (71) which correspond to the non-benzenoid forms of (72). The elusive property of aromaticity is therefore possessed by both tautomers, although not necessarily by both equally. When the carbonyl oxygen of (72) is replaced by less electronegative atoms, as in the imine tautomers of amino heterocycles, or the methylene tautomers of methyl derivatives, the tendency towards polarization in forms corresponding to (72b) and (72c) is considerably less, and the amino and methyl tautomers are therefore favoured in most instances. 

The Tautomerism of Heterocycles J. Elguero etal., Adv. Heterocycl. Chetn., Suppl. 1,1976. Ring-Chain Isomeric Transformations of Hydroxy-, Amino-, and Mercapto-Derivatives of Carbonyl Compounds and Their Heteroanalogues R. Valters, Russ. Chem. Rev. Engl. Transl.), 1974, 43, 665-678. 

Among tautomerizable derivatives, 7-hydroxy compounds have been confirmed to exist largely in the 4H-7-oxo form (e.g., 2 cf. Section III,E,1) that, therefore, will be used in this review. For other hydroxy as well as mercapto and amino TPs, when the exact position of tautomeric equilibria is uncertain, the most probable or the respective authors form will be depicted. 

Studies on the tautomerism of pyridazines with potential tautomeric groups have continued. On the basis of recorded ionization constants and UV spectra of 3,4,5-trimercaptopyridazine and its derivatives, it is concluded that the compound exists as 3,4-dimercaptopyridazine-5(2f/)-thione. Tautomerism of hydroxy- and mercaptopyridazines was investigated with the aid of the corresponding anhydro bases as reference compounds. They exist predominantly in the -one or -thione forms. Similarly, the 3-mercapto-pyridazine-6(l/f)-thione structure in aqueous solution has been redeter-... 

Quinoxaline and 2-methylquinoxaline react with diphenylcyclo-propenone (75) to give the products 76, analogous to that obtained from the reaction of 75 with pyrazine (see Chapter XIX). The formulation of the products as 1-hydroxy rather than 1,5-dihydro-1-oj o compounds is discussed in Section II. The thioxo analogue of 75 give the 1-mercapto derivative 77 on reaction with quinoxaline. No spectral details are given to permit discussion of possible tautomerism of this compound to the 1,5-dihydro-1-thioxo derivative. 

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