Side-Chain Reactivity of Thiophenes

The large success of the Hammett equation in relating and systematizing the side-chain reactivities of meta- and poro-substituted benzenes has stimulated similar studies in the thiophene series. 

The rate of saponification of ethyl 2-thenoate, in contrast to ethyl 3-thenoate, was found to be considerably slower than predicted from the pKa of the acid, showing that the reactivities of thiophenes do not parallel those of benzene. The first explanation, that this was produced by a steric effect of the ring sulfur similar to the case in or /lo-substituted benzenes and in ethyl 1-naphthoate, could not be upheld when the same effect was found in ethyl 2-furoate. It was later ascribed to a stereospecific acid strengthening factor, involving the proper relation of the carboxylic hydrogen and the heteroatom, as the rate of saponification of 2-thienylacrylic acid was in agreement with that predicted from the acid constants.  

So-called aryl values have been introduced by Imoto et ai. - for the piu pose of systematizing the reactivities of different aromatic systems by means of the linear free-energy relationship, which however, could not be applied to the decomposition rates of heterocyclic acyl azides in toluene.  

From measurements of acid constants, and rates of esteri- 

The aforementioned exception and the rather limited experimental material available do not allow any conclusions about the general applicability of the Hammett equation, using the same a- and p-values as for benzenes, to be drawn with certainty. The present author has pointed out that large deviations should be expected with strong - -M-substituents, as is also indicated from the rates of alkaline hydrolysis of methyl 5-amino- and 5-acylamino-2-thenoates. From the chemical shifts in the NMR spectra of thiophenes and benzenes it appears that another set of cr-values should be used in the thiophenes series which seems plausible since the transmission of the sub- 

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As well as the previous chapter on the Hammett equation,1 the importance of the approach has found expression in specific areas in other contributions to these volumes side chain reactivities of thiophenes 17 tautomerism 18 reactions of azines with nucleophiles 19,20 formation of benzofuroxans by decomposition of o-nitrophenyl azides 21 acid dis-... 

Thermal reaction of halothiophenes with thiyl radicals 90UK1338. Side-chain reactivity of thiophenes 86HC(44,3)975. 

Ch. 5 Side Chain Reactivity of Thiophenes Thenyl Derivatives... 

The greatest difference observed between the side-chain reactivities of selenophene and thiophene derivatives was in the reaction of aldehydes with aniline (cf. Eq. 13), a ratio of 4.2. 

Campaigne et al. have used 3-thenyl bromide obtained by benzoyl peroxide-catalyzed, side-chain bromination of 3-methylthiophene with A -bromosuccinimide, as a starting material for 3-substituted thiophenes. - 22 3-Methylthiophene is now prepared commercially from itaconic acid. The reactive halogen in 3-thenyl bromide could be directly reacted with a variety of nucleophiles, such as cyanide, or malonate, to give more complex 3-substituted compounds. 3-Thenyl bromide was converted by the Sommelet reaction to 3-thio-phenealdehyde which, with silver oxide, was oxidized to 3-thio-... 

In Table II the pK s of the 2- and 3-carboxylic acids of thiophene, furan, and pyrrole are reported. While pyrrole carboxylic acids, like the alkoxy- and amino-substituted benzoic acids, are weaker, thiophene- and furan carboxylic acids, like the chloro-and bromobenzoic acids, are stronger than unsubstituted benzoic acid. This behavior is confirmed by other side-chain reactivity data.41... 

Side-chain Reactivities.—Several papers quantitatively treating the influence of the thiophen ring on side-chain reactivity have appeared. The reaction of 5-substituted 2-thenoyl chlorides with aniline in benzene follows second-order kinetics. The values of the Hammett p-constants are greater than that for the benzoylation reaction, indicating that the thiophen nucleus is more efficient than the benzene ring in relaying the electronic effects of the substituent to the reaction centre. The rate of the reaction of 3-thenoyl chloride and of thiophen-2-sulphonyl chloride with substituted anilines has also been studied, and the Hammett equation applied to the rate... 

Rate data are also available for the solvolysis of l-(2-heteroaryl)ethyl acetates in aqueous ethanol. Side-chain reactions such as this, in which a delocalizable positive charge is developed in the transition state, are frequently regarded as analogous to electrophilic aromatic substitution reactions. In solvolysis the relative order of reactivity is tellurienyl> furyl > selenienyl > thienyl whereas in electrophilic substitutions the reactivity sequence is furan > tellurophene > selenophene > thiophene. This discrepancy has been explained in terms of different charge distributions in the transition states of these two classes of reaction (77AHC(21)119>. 

This activation of the ortho position is most strikingly illustrated in the reactivity of 2,5-dimethylthiophene, which competitive experiments have shown to undergo the SnCb-catalyzed Friedel-Crafts reaction more rapidly than thiophene and even 2-methylthiophene. The influence of the reagent on the isomer distribution is evident from the fact that 2-methoxythiophene is formylated and bromi-nated (with A -bromosuccinimide) only in the 5-position. Similarly, although 3-bromo-2-methylthiophene has been detected in the bromi-nation of 2-methylthiophene with bromine, only the 5-isomer (besides some side-chain bromination) is obtained in the bromination of alkylthiophenes with A -bromosuccinimide. ° However, the mechanism of the latter type of bromination is not established. No lines attributable to 2-methyl-3-thiocyanothiophene or 2-methyl-3-chIoro-thiophene could be detected in the NMR spectra of the substitution products (5-isomers) obtained upon thiocyanation with thiocyanogen or chlorination with sulfuryl chloride. 2-Methyl- and 2-ethyl-thiophene give, somewhat unexpectedly, upon alkylation with t-butyl chloride in the presence of Feds, only 5-t-butyl monosubstituted and... 

Nucleophilic substitution reactions in the selenophene series have attracted some interest. Debromination of bromonitro compounds [(50, X = S, Se) and (53, X = S, Se)] with sodium thiophenoxide and sodium selenophen-oxide72 was studied. Selenophene compounds were four times more reactive than the thiophene derivatives. The position of attack, a or /), had very little influence on the rate ratio. The kinetics of the side-chain nucleophilic reactions of selenophene derivatives, shown in Scheme 4, has been reported.7 3... 

The partial rate factors af and /3f for the a- and /3-positions of thiophene have been calculated for a wide range of electrophilic reactions these have been tabulated (71 AHC(13)235, 72IJS(C)(7)6l). Some side-chain reactions in which resonance-stabilized car-benium ions are formed in the transition states have also been included in this study. A correspondence between solvolytic reactivity and reactivity in electrophilic aromatic substitution is expected because of the similar electron-deficiency developed in the aromatic system in the two types of reactions. The plot of log a or log /3f against the p-values of the respective reaction determined for benzene derivatives, under the same reaction conditions, has shown a linear relationship. Only two major deviations are observed mercuration and protodemercuration. This is understandable since the mechanism of these two reactions might differ in the thiophene series from the benzene case. 

The only available data concern some a-carbonium ion side-chain reactions (hydrolysis of <-cumyl chlorides and p-nitrobenzoates) they reveal that the substitution of nitrogen for a CH group, in furan, thiophene, or pyrrole, leads to a fairly uniform reduction in reactivity at the 2-position.211... 

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