Tautomeric form

Thiourea, unlike urea, readily reacts in the tautomeric form (I) in the presence of suitable reagents, particularly alkyl halides thus benzyl chloride reacts with... 

The tautomerism shown by the pyrazolones is of considerable interest. Thus the above methyl"-phenyl pyrazolone when fused or in solution can exist in the tautomeric forms (C), (D), and (E). 

The nitroparaffiiis in which the nitro group is attached to a primary or secondary carbon atom exist in tautomeric forms, for example ... 

A-2-Thiazoline-4 one may exist in three tautomeric forms (174a. 174b. and 174c) (Scheme 90). 

A-2-Thiazoline-5-one may exist in three tautomeric forms (Scheme 108). The tautomeric equilibrium has been studied by H NMR (446. 453. 457. 464). infrared (453. 464-466). and ultraviolet (453, 464) spectros-... 

Similar to their 2-hydroxy analogs, these compounds exhibit properties (cf. Chapter VII) that are characteristic of each of the two possible tautomeric forms the thiol (163a) and the thione or 2-thioxo-A-4-thiazoline (163b). 

These relationships are general Hydroxyl substituted purines and pyrimidines exist in their keto forms ammo substituted ones retain structures with an ammo group on the ring The pyrimidine and punne bases m DNA and RNA listed m Table 28 1 follow this general rule Beginning m Section 28 7 we 11 see how critical it is that we know the cor rect tautomeric forms of the nucleic acid bases... 

In most reactions diketene appears to react as acetylketene or one of its tautomeric forms. This is one of the reasons for the correct stmcture of diketene being firmly established only in 1952, 45 years after its discovery (97,98). 

The main appHcation of nmr in the field of pyrazolines is to determine the stereochemistry of the substituents and the conformation of the ring. For pyrazolones, nmr is useful in estabUshing the stmcture of the various tautomeric forms. Table 2 summarizes the chemical shifts of a few representative derivatives. 

Pyrazolones. The 0x0 derivatives of pyrazolines, known as pyrazolones, are best classified as follows 5-pyrazolone, also called 2-pyrazolin-5-one [137-44-0] (36) 4-pyrazolone, also called 2-pyrazolin-4-one [27662-65-3] (37) and 3-pyrazolone, also called 3-pyrazolin-5-one [137-45-1] (38). Within each class of pyrazolones many tautomeric forms are possible for simplicity only one form is shown. 

Substitution at decreases the possible number of tautomers for 3-pyrazolones, two tautomeric forms are possible, (39) and (40), which in nonpolar solvents are both present in about the same ratio. 5-Pyrazolones exhibit similar behavior. 

Hydroxyisoquinolines. Hydroxy groups in the 5-, 6-, 7-, and 8-position show phenoHc reactions for example, the Bucherer reaction leads to the corresponding anainoisoquinolines. Other typical reactions include the Mannich condensation, azo-coupling reactions, and nitrosation. Both 0-methyl and /V-methyl derivatives are obtained from the methylation of 1-hydroxyisoquinoline, indicating that both tautomeric forms are present. Distillation of various hydroxy compounds, eg, 1- and 4-hydroxyisoquinoline, with zinc dust removes the oxygen. Treatment of 1-isoquinolinol with phosphoms tribromide yields 1-bromoisoquinoline [1532-71 -4] (178). 

In mordant dyes, phenols, naphthols, and enolizable carbonyl compounds, such as pyrazolones, are generally the couplers. As a rule, 2 1 metal complexes are formed ia the afterchroming process. A typical example of a mordant dye is Eriochrome Black T (18b) which is made from the important dyestuff iatermediate nitro-l,2,4-acid, 4-amiQO-3-hydroxy-7-nitro-l-naphthalenesulfonic acid [6259-63-8]. Eriochrome Red B [3618-63-1] (49) (Cl Mordant Red 7 Cl 18760) (1, 2,4-acid — l-phenyl-3-methyl-5-pyrazolone) is another example. The equiUbrium of the two tautomeric forms depends on the nature of the solvent. 

Xanthene dyes (qv) can be either acidic or basic. Acid xanthenes are known to exist in two tautomeric forms. The phenoHc type, or fluorans, are free-acid stmctures such as D C Orange No. 10 (17b) and D C Red No. 21 (17c). Most have poor water solubHity. In contrast to these, the quinoids or xanthenes are usuaHy the highly water-soluble sodium salt counterparts of the fluorans such as D C Orange No. 11 (18) and D C Red No. 22 (21a). Presendy, there are no certifiable basic xanthene colorants. 

When the lone electron pair is protonated, the nitrogen chemical shift moves by ca. 100 p.p.m, to higher field. Large upheld shifts are also found when a compound exists in a tautomeric form with a proton on the nitrogen. The nitrogen NMR spectrum is often of considerable value in studies of tautomerism of this type. 

Tautomerism questions arise with hydroxyphenazines and quinoxalines which contain hydroxyl groups in the aromatic ring. Does 5-hydroxyquinoxaline (62) show any tendency to exist as the tautomer (63) or 1-hydroxyphenazine (64) to exist as (65) Analogous tautomeric forms can also be written for 6-hydroxyquinoxaline and 2-hydroxyphenazine. 

The effect of substituents on the reactivity of heterocyclic nuclei is broadly similar to that on benzene. Thus mem-directing groups such as methoxycarbonyl and nitro are deactivating. The effects of strongly activating groups such as amino and hydroxy are difficult to assess since simple amino compounds are unstable and hydroxy compounds exist in an alternative tautomeric form. Comparison of the rates of formylation and trifiuoroacetylation of the parent heterocycle and its 2-methyl derivative indicate the following order of sensitivity to substituent effects furan > tellurophene > selenophene = thiophene... 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

This can be achieved by an indirect method. The lithio derivative is first reacted with a borate ester. Sequential acid hydrolysis and oxidation yields the corresponding hydroxy derivative. This procedure is illustrated by the conversion of 2-lithiobenzo[6]thiophene to 2-hydroxybenzo[6]thiophene, which exists predominantly in the 2(3//)-one tautomeric form (200) <70JCS(C)1926). 

Microwave spectroscopy distinguishes readily between possible tautomeric forms of 1,2,3-and 1,2,4-trlazole, which are both in the li-f-form. In tetrazole both the li-f-and 2//-forms are detected (74PMH(6)53). 

For the NH azoles (Table 3), the two tautomeric forms are usually rapidly equilibrating on the NMR timescale (except for triazole in HMPT). The iV-methyl azoles (Table 4) are fixed chemical shifts are shifted downfield by adjacent nitrogen atoms, but more by a pyridine-like nitrogen than by a pyrrole-like iV-methyl group. 

Annular tautomerism (e.g. 133 134) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (133 R = H) and pyrazole (135 R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. Flowever, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (136) than in (137), and UV spectral comparisons show that benzotriazole exists predominantly as (136). 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

The 4-substituted analogs can exist in two uncharged tautomeric forms (141) and (142) and, in addition, in the zwitterionic form (143), but all the evidence shows that the compounds all exist predominantly in the NH2 or OH form (141). 

Substituted 1,3-azoles exist in two non-charged tautomeric forms (156) and (157) together with the zwitterlonic form (158). 5-Substltuted 1,3-azoles also exist in forms (159) and (160) together with the zwitterlonic forms (161). Some results are summarized in Table... 

Together with pyridones, the tautomerism of pyrazolones has been studied most intensely and serves as a model for other work on tautomerism (76AHC(Sl)l). 1-Substituted pyrazolin-5-ones (78) can exist in three tautomeric forms, classically known as CH (78a), (DH (78b) and NH (78c). In the vapour phase the CH tautomer predominates and in the solid state there is a strongly H-bonded mixture of OH and HN tautomers (Section 4.04.1.3.1). However, most studies of the tautomerism of pyrazolones correspond to the determination of equilibrium constants in solution (see Figure 20). 

Aromatic pyrazoles and indazoles, in the broad sense defined in Sections 4.04.1.1.1 and 4.04.1.1.2, will be discussed here. Tautomerism has already been discussed (Section 4.04.1.5) and acid-base equilibria will be considered in Section 4.04.2.1.3. These two topics are closely related (Scheme 10) as a common anion (156a) or a common cation (156b) is generally involved in the mechanism of proton transfer (e.g. 78T2259). For aromatic pyrazoles with exocyclic conjugation there is also a common anion (157) for the three tautomeric forms... 

With 3- and 4-substituted isoxazoles the tautomeric form normally present is the XH tautomer, (13 X = O) and (14 X = O, N) respectively. However, other influences need to be considered as in cycloserine (IS), which exists as a zwitterion, as does 5-amino-3-hydroxy-isoxazole (16). 

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