Thiophene reactivity comparison

The reactions of furansulfonyl chlorides with anilines (entry 11)123 in MeOH yield a linear Bronsted plot with fix =0.51, which indicates an Sw2 mechanism rather than a stepwise process. This value is quite similar to those found for the reactions of anilines with benzenesulfonyl chloride (0.63)117, with 2-thiophenesulfonyl chloride (0.53)124 and with 3-thiophenesulfonyl chloride (0.54)125. Thus their anilinolysis mechanism is also expected to be S/y2. The reaction rate therefore depends not only on the nucleophile basicity but also on the substrate reactivity. Comparison of the reaction rates leads to the following reactivity order for the Ar moiety benzene > 3-thiophene > 3-furan > 2-furan > 2-thiophene. This reactivity sequence follows the order of the resonance interaction between the... 

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I " in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan > thiophene > pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together. ... 

Soon after thiophene was discovered by Victor Meyer, reports from his group gave the first examples of halogenated thiophenes - dibromothiophene (now known to be 2,5-dibromothiophene) and monoiodothiophene [77]. Monoiodothiophene (now known to be 2-iodothiophene) was synthesised from a mixture with benzene isolated from coal tar containing 50-60% of thiophene ( raw thiophene ). Here the higher reactivity of thiophene in comparison to benzene in halogenations was observed and used. Thus for benzene, iodination requires elevated temperatures, but thiophene was iodinated at room temperature. It was found that 2-iodothiophene can be synthesised either by the treatment with a mixture of iodine and iodic acid or... 

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... 

The acid cleavage of the aryl— silicon bond (desilylation), which provides a measure of the reactivity of the aromatic carbon of the bond, has been applied to 2- and 3-thienyl trimethylsilane, It was found that the 2-isomer reacted only 43.5 times faster than the 3-isomer and 5000 times faster than the phenyl compound at 50,2°C in acetic acid containing aqueous sulfuric acid. The results so far are consistent with the relative reactivities of thiophene upon detritia-tion if a linear free-energy relationship between the substituent effect in detritiation and desilylation is assumed, as the p-methyl group activates about 240 (200-300) times in detritiation with aqueous sulfuric acid and about 18 times in desilylation. A direct experimental comparison of the difference between benzene and thiophene in detritiation has not been carried out, but it may be mentioned that even in 80.7% sulfuric acid, benzene is detritiated about 600 times slower than 2-tritiothiophene. The aforementioned consideration makes it probable that under similar conditions the ratio of the rates of detritiation of thiophene and benzene is larger than in the desilylation. A still larger difference in reactivity between the 2-position of thiophene and benzene has been found for acetoxymercuration which... 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

For both nucleophiles, 2,5-dinitrofuran is the most active substrate, the thiophene derivative follows. On the other hand, the relative reactivity of 1-methyl-2,5-dinitropyrrole and 1,4-dinitrobenzene depends on the nature of the nucleophile. For the 4-MeC6H4S anion, the former is more active by about two powers of ten, but in the piperidinolysis reaction the 1,4-benzene is superior. These phenomena appear to be caused by differences in the polarizability of both substrate and nucleophiles. p-Tolylthiolate anion is a softer nucleophile in comparison with piperidine and the pyrrole system is certainly more polarizable than the benzene molecule. Therefore soft-soft interaction of 1-methyl-2,5-dinitropyrrole with 4-MeC6H4S and hard-hard interaction of 1,4-dinitrobenzene with piperidine should occur easier than interactions between reagents with opposite types of softness and hardness. 

Thiophene is far more reactive than benzene in electrophilic substitution reactions. Reaction with bromine in acetic acid has been calculated to be 1.76 x 109 times faster than with benzene (72IJS(C)(7)6l). This comparison should, of course, be treated with circumspection in view of the fact that the experimental conditions are not really comparable. Benzene in the absence of catalysts is scarcely attacked by bromine in acetic acid. More pertinent is the reactivity sequence for this bromination among five-membered aromatic heterocycles, the relative rates being in the order 1 (thiophene) and 120 (furan) or, for trifluoroacetylation, 1 (thiophene), 140 (furan), 5.3 xlO7 (pyrrole) (B-72MI31300, 72IJS(C)(7)6l). Among the five-membered heteroaromatics, thiophene is definitely the least reactive. 

Dinitrothiophene undergoes displacement of one of the N02 groups on treatment with piperidine. Comparison of the rates of piperidino-denitration of the dinitro derivatives of furan (404), thiophene (405), pyrrole (406) and benzene (407) shows the following order of reactivity (404) > (405) > (407) > (406) (76JOC2824). 

C(8a)—C(9) are elongated. The common bond C(3a)—C(9a) is also lengthened. A comparison of the 7r-electron densities reveals that all three procedures show almost the same trends. The calculated 7r-electron densities for thieno[2,3-6]quinoline (378) and thieno[3,4-6]quinoIine (379) do not differ significantly from the corresponding thienopyridines provided that the same set of parameters is used. Calculated reactivity indices indicate that electrophilic substitution reactions should occur predominantly in the thiophene unit. 

Calculations have been carried out to estimate the relative reactivities of the isomeric thienothiophenes in comparison with thiophene or naphthalene. The localization energy is expected to be the most adequate index of reactivity (76AHC(19)123). 

Electrophilic substitution reactions of 5-hydroxybenzo[6]thiophene have been investigated in some detail. The 4-position is the most reactive toward nitration,152 nitrosation,497 bromination,422 and formylation (Duff procedure).338 Dibromination in the presence of acetate ion affords 4,6-dibromo-5-hydroxybenzo[6]thiophene,421,422, 497 and not the 3,4-dibromo derivative, as previously believed.542 Dichlorination similarly affords the 4,6-dichloro derivative,421 and not 4,4-dich loro-4,5-dihydrobenzo[6]thiophen-5-one, as reported earlier by Fries d al.542 An interesting comparison can be made between the behavior of 5-hydroxy benzo[6]thiophene and 2-naphthol in electrophilic substitution reactions. It is clear that both positions ortho to the hydroxyl group in 5-hydroxybenzo[6]thiophene are attacked, in contrast to 2-naphthol, where only the 1-position is attacked even in the presence of an excess of the reagent. Disubstitu-... 

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... 

Concerning the comparison among thiophene, furan, and pyrrole, the reactivity order was established mainly on the basis of qualitative criteria. 

On the basis of these qualitative criteria the following order of reactivity was universally established benzene[Pg.263]

In the tin tetrachloride-catalyzed acetylation by acetic anhydride in dichloroethane, furan is more reactive than thiophene by a factor of 11.9 as determined by a competitive method. The use of iodine as catalyst does not substantially alter the reactivity ratio.130 The comparison could not be extended to pyrrole, because of the interaction of this substrate with Friedel-Crafts catalysts139 (see discussion in Section II, E). 

Later, Linda and Marino84, 90, 180 were able to compare the relative reactivities of all four fundamental systems (furan, thiophene, selenophene, and pyrrole) toward bromination by molecular bromine in acetic acid. Unfortunately, the comparison could not be made on the unsubstituted rings for the following reasons first, the rates of substitution for furan and pyrrole were too high to be followed by standard kinetic techniques second, furan and pyrrole undergo ring fission and/or polymerization under the influence of the hydrobromic acid formed in the reaction finally, furan tends to give addition as well as substitution products in the reaction with bromine.1818. 

Recently the overall reactivities relative to the monocyclic rings have been determined for a number of reactions77 by kinetic or competitive procedures. The data, reported in Table XVIII, show that fusion with a benzene ring produces an overall decrease in reactivity in both systems. The decrease is much more pronounced for furan than for thiophene ring. As a consequence of this, the overall reactivities of benzofuran and benzothiophene are nearly equal in all the substitutions for which quantitative data are available (column 3 of Table XVIII for a useful comparison the relative reactivities of the monocyclic rings in the same reactions are also reported in column 4). 

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