Thiophenes hydrogen exchange

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

The kinetic isotope effect kD kT for hydrogen exchange of ferrocene in both trifluoroacetic acid-acetic acid and trifluoroacetic acid-dichloromethane has been measured558. In the former medium (1 1 molar ratio at 25 °C) kD kT was 1.2—1.3, which was less than that obtained for the 2 position of thiophene (D) = 1,200 xlO-7, ki(T) = 660xl0-7, kD kT = 1.9. It is also lower than that obtained for pentamethylbenzene fcx(D) = 3,300 x 10-7, Art(T) =... 

Two excellent reviews <71AHC(13)235, 72IJS(C)(7)6l) have dealt with quantitative aspects of electrophilic substitution on thiophenes. Electrophilic substitution in the thiophene ring appears to proceed in most cases by a mechanism similar to that for the homocyclic benzene substrates. The first step involves the formation of a cr-complex, which is rate determining in most reactions in a few cases the decomposition of this intermediate may be rate determining. Evidence for the similarity of mechanism in the thiophene and benzene series stems from detailed kinetic studies. Thus in protodetritiation of thiophene derivatives in aqueous sulfuric and perchloric acids, a linear correlation between log k and —Ho has been established the slopes are very close to those reported for hydrogen exchanges in benzene derivatives. Likewise, the kinetic profile of the reaction of thiophene derivatives with bromine in acetic acid in the dark is the same as for bromination of benzene derivatives. The activation enthalpies and entropies for bromination of thiophene and mesitylene are very similar. 

A number of kinetic studies on hydrogen exchange of derivatives of furan,53 thiophene,53-58 pyrrole,53 selenophene,59 imidazole,60 oxazole,60 thiazole,80 and indole61 have been reported. The kinetic picture is the same as for benzene derivatives reactions follow pseudo first-order kinetics and the k1 values increase markedly as the acidity of the medium increases. 

Ostman and Olsson68 have determined the kinetic isotope effect in the isotopic exchange of thiophene, by comparing the rates of protodedeuteration and protodetritiation at both positions of the ring. The values obtained for the D/fcT ratios are 1.94 for the a position and 1.70 for the )3 position. Thus the ratio kD/kT seems to increase with increasing reactivity, a tendency already observed in the hydrogen exchange of benzene and toluene.64... 

Until a few years ago, no quantitative comparison of overall reactivities in electrophilic substitution of the fundamental five-membered rings was available. Only the reactivity of thiophene relative to benzene had been measured quantitatively in several electrophilic substitutions bromination,72 chlorination,72 nitration,121 hydrogen exchange,57 protodesilylation,174 and mercura-tion.121... 

V-Benzylthieno[3,2-6]pyrrole (18) was lithiated and upon treatment of the lithio derivative with methyl chloroformate, 2-methoxycarbonyl-lV-benzylthieno[3,2-f>]pyrrole (51) was obtained (Scheme 10). The a-proton in the thiophene ring is more reactive towards metal-hydrogen exchange compared to the proton at C-5. 

Relative Rates of 2-Substitution of Thiophenes RC4HjS in Acid-Catalyzed Hydrogen Exchange... 

Many thiophenes have been lithiated en route to other derivatives. The lithiation reaction [Eqs (6.1) and (6.2)] is related to base-catalyzed hydrogen exchange, but differs from it in the relative rates of steps (6.1) and (6.2), the latter being obviously faster and non-rate-determining for lithiation. 

Substituents produce a larger effect than they do in benzene, indicating that the transmission of electronic effects is greater in thiophene. This is in contrast with the results obtained in hydrogen exchange and apparent results obtained in a number of other reactions. 

Nevertheless, it is approximately true that in reactions of average demand for resonance, cr furan) - crt(thiophene) is 0.1, cr - cr, (furan) is 0.45, and crt - o, (thiophene) is 0.40. Reasonably consistent values of a2 for furan, thiophene, selenophene, and tellurophene are -0.91, -0.81, -0.88, and -0.90, respectively the best 0-3 values for furan and thiophene are -0.45, and -0.43, respectively. No data are available for the relative reactivities of the 3-positions of selenophene or tellurophene. The 3-position of pyrrole is slightly more reactive than the 2-position in hydrogen exchange, but the reactivities are so close that under different demands for resonance, the reactivity order can be inverted. 

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