3- Hydroxythiophenes, tautomerism

In the absence of oxygen, these thiolene-2-ones are rather stable and have been kept at 0°C for several months. 3-Hydroxythiophene, on the other hand, which has been prepared in low yield from 3-thio-phenemagnesium bromide in the same way as the 2-isomer, or through decarboxylation of 3-hydroxy-2-thiophenecarboxylic acid, "" is very unstable. Its IR spectrum indicates that it also exists as a tautomeric mixture largely in its enolic form. ... 

The UV spectrum of 5-phenyl-3 hydroxythiophene is very similar to that of its methyl ether in alcoholic solution, indicating that it exists largely in the enol form in this solvent. The same coincidence of the wavelength maxima was also obtained for 5-phenyl-2-hydroxy-thiophene and its methyl ether. In chloroform solution, the maxima were shifted toward longer wavelengths, suggesting that the tautomeric equilibrium in this solvent is displaced more toward the keto form. ... 

Hydroxythiophenes 56 have two possible keto tautomers (57 and 58) [for review see (86HC1)]. As has been pointed out earlier (76AHCS1, p. 229), the tautomerism of 5-substituted eompounds was extensively studied by Lawesson and eoworkers (63T1867) and by Hornfeldt (63MI1 68MI1). For 5-alkyl eompounds, only the keto forms were present, whereas with R = phenyl, thienyl and ethoxyearbonyl substantial amounts of the enol forms were deteeted. Computations for the parent system (R = H) showed that the 4 -thiobutenolide of type 57 is most stable (Table VII). 

The ionization potentials, using mass spectrometry, for both 2-hydroxy-and 3-hydroxythiophenes have been compared with data for compounds derived from either tautomeric form in order to analyze the tautomeric composition.124 125 In the 2-hydroxy-substituted system the enol isomer could not be detected. Of the two possible unsaturated lactones the oc,/l-unsaturated form was the major isomer. In the 3-hydroxy-substituted case both the oxo form and the enol form are important. The position of the equilibrium was compared with those of the corresponding furan and sele-nophene systems for both isomers. 

Equilibrium and rate constants for the keto-enol tautomerization of 3-hydroxy-indoles and -pyrroles are collected in Table 32 (86TL3275). The pyrroles ketonize substantially (103-104 times) faster than their sulfur or oxygen analogues, and faster still than the benzo-fused systems, indole, benzofuran, and benzothiophene. The rate of ketonization of the hydroxy-thiophenes and -benzothiophenes in acetonitrile-water (9 1) is as follows 2-hydroxybenzo[b]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxybenzo[/ Jthiophene > 3-hydroxythiophene. 3-Hydroxythiophene does not ketonize readily in the above solvent system, but in 1 1 acetonitrile-water, it ketonizes 6.5 times slower than 2-hydroxythiophene (87PAC1577). 

The high stability of the carbonyl double bond and the possibility for hydrogen bond formation probably accounts for the 2-hydroxythiophene derivative (101) occurring chiefly in the tautomeric form (102) rather than (103) (equation 24). 

The tautomerism of hydroxythiophenes has been discussed in Section 3.01.6. In nucleophilic substitution reactions the p-nitrophenoxy group has been extensively investigated as a leaving group in order to give a unified picture, details of such studies have been included in Section 3.14.3.8. 

A number of important families of heterocycles belong to this class and many of the important systems are oxo derivatives. 2-Hydroxyfuran 64 exists almost exclusively as the equilibrating 3H- and 5//-furan-2-one tautomers 66 and 67. Tautomerism favoring the nonconjugated isomers also occurs in hydroxypyrroles and hydroxythiophenes. Similar behaviour is observed with simple amino derivatives 2-aminofuran 65 is too unstable to be detected <2006AHC (92)1 >. The 3-oxo tautomer 68 is the preferred form of 3-hydroxyfuran. 

The 2-substituted hydroxythiophene systems 186 (Scheme 11) gives rise to three different tautomeric forms. In contrast to phenol, 2-hydroxythiophene exists almost exclusively in one of its carbonyl forms. These forms predominate because of the very stable thiolactone moiety. Several papers have discussed how different substituents influence the tautomeric equilibrium of this system, particularly for monosubstituted compounds. 

For 3-substituted hydroxythiophene systems 189, there are only two tautomeric structures possible, one hydroxy form and one carbonyl form. Many papers have shown that the hydroxy form dominates these equilibria . 

Hydroxy thiophenes are very unstable compounds <1996CHEC-II(2)483>. 2-Hydroxythiophenes are generally found in the tautomeric forms 186-188, while the 3-hydroxy isomer can exist in either the hydroxy form 189 or the keto form 190. Although some of these systems could exist as mixtures or exclusively in the keto form, we shall generically refer to them as hydroxythiophenes for simplicity. 

Halo substituents do not influence the general tautomeric patterns of the hydroxythiophenes <2000J(P2)1453>. The trichlorinated hydroxythiophenes are stable when kept under nitrogen. The hydroxythiophenes with a bromine substituent, however, started to polymerize quite rapidly, even when kept at temperatures below 0 °C under nitrogen. The carbonyl structure of 2,5-dihydrothiophen-2-one 198bis the only detectable tautomer of compound 198. 

Quantum-chemical calculation of the relative stabilities <1989JST(184)179> of tautomeric forms B and C of substituted 2-hydroxy- and 2-mercaptothiophenes have been carried out by the AMI and PM3 methods. The calculation results shown in Table 78 indicate a definite preference for the thiol form in the case of 2-thiophenethiols 248 and similar A77 values for the formation of all three tautomeric forms in the case of 2-hydroxythiophenes, which corresponded to the experimental data . The effect of substituents on the relative stabilities for hydroxy- and mercaptothiophenes is identical and in complete qualitative accord with the empirical data obtained for hydroxythiophenes substituents at C-3 and C-4 stabilize to form 249, while substituents at C-5 stabilize to form 250 (Scheme 20) <1997CHE1047>. 

Table 78 Quantum-chemical calculation of the relative stabilities of tautomeric forms 248-250 of R-substituted 2-thiophe-nethiols and analogously substituted potential 2-hydroxythiophenes 186 ...

Thus, 5-amino-2-hydroxythiophene may exist in three tautomeric forms, 264-266 (Scheme 25). 

A convenient synthesis of the 2-aryl-5-hydroxythiophen system consists of the reaction of the corresponding butenolides with sodium hydrosulphide-hydrogen chloride, 3-Hydroxy-4-anilinomethylthiophen exists in the stable tautomeric form (25)." The allyl ether of dimethyl 3-hydroxythiophen-... 

The inclusion of alkyl groups both stabilise the oxy-compounds and the double bond to which they are attached. In these more stable compounds alternative tautomers are found, thus 5-methyl-2-hydroxythiophene exists as a mixture (actually separable by fractional distillation ) of the two enone tautomers. / -Hydroxythiophenes are even more unstable than a-hydroxythiophenes 3-hydroxy-2-methylthiophene exist as a mixture of hydroxyl and carbonyl tautomeric forms with the former predominating. ... 

Initial reports of carboxy substituents on 3-hydroxythiophenes indicated that the compounds all existed in the hydroxy form <65X3331,67X871,68CJC2255, 71X3839), irrespective of the position of the substituent. However, reports have indicated the existence of tautomeric mixtures of both forms <70JCS2409>. 

JCS(C)243i>. 2-Thiophenethiol (120) is not stable and slowly solidifies on standing. Although one would expect the disulfide (122) to form due to air oxidation, it is the dimer (123) which is actually formed. It is possible that there is a slow tautomerism to the mercapto form (121) which is then susceptible to Michael addition by (120) to yield the dimer (123) which can be converted back to (120) <89JOC3223>. The possibility of (121) forming was corroborated by the fact that Michael addition of (120) with 2-hydroxythiophene (which exists exclusively in the keto form (88)), afforded the dimer (124) (Scheme 9). 

Thiophene-1-oxides Thiophene-1,1 -dioxides. 2.1 Reaction with nucleophiles. 2.2 Cycloaddition reactions. 2.3 Other reactions Thiophene S,N-ylides and S,C-ylides. 3.1 Cycloaddition reactions of S,N-ylides and S,C-ylides. 3.2 Cyclopropanation reactions of S,C-ylides. 3.3 Thermal transformations of thiophene S,N- and S,C-ylides Oxothiophenes Tautomeric with Hydroxythiophenes. 4.1 Tautomerism. 4.2 Alkylation and acylation. 4.3 Condensation reactions at the methylene group. 4.4 Halogenation. 4.5 Oxidative coupling. 4.6 Cycloaddition. 4.7 2,3-Diones 4 Sulfoxides and sulfones. 4.9 Photochemistry. 4.10 Macrocyclic polyethers... 

In this section, the chemistry of thiophene-3(2//)-ones (243) and thiophene-2(5/0-ones (244) is discussed (Scheme 46). When R = H, these are tautomeric with 3-hydroxythiophenes and 2-hydroxythiophenes, respectively. For the sake of convenience, even the chemistry of nonenolizable x,x-dialkylthiophenones (R, R H) is included in this section. Earlier, these subjects had been dealt with in CHEC-I under the section on the reactivity of O-linked substituents <84CHEC-I(4)74i>. 

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... 

Acid-catalysed dealkylation gave the corresponding dihydroxythiophen systems. The predominant tautomeric structure was determined by spectroscopic methods. 5-Substituted 2-cyano-3-hydroxythiophens, prepared through ring-closure reactions, were shown to exist as intramolecu-larly hydrogen-bonded hydroxy-forms. ... 

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