Thiophenes, carbon atom reactivity

Pathway III of Fig. 26 has been demonstrated for thiophene and benzo-thiophene with Ir complexes (4) and for all thiophenes, including dibenzo-thiophene, with Rh complexes (94, 95). These oxidative additions appear to be influenced by substituents present on the carbon atoms adjacent to the sulfur atom. Insertion between sulfur and the unsubstituted carbon is highly preferred. For 2-methylthiophene the exclusive product is the 1-5 bond insertion product, whereas for 3-methylthiophene, no preference for insertion was observed (1-2 and 1-5 bond insertion products were equal). In competitive studies, thiophene was found to be about twice as reactive as 2,5-dimethylthiophene. This behavior is similar to that observed for relative reaction rates of substituted thiophenes observed with conventional HDS catalysts. Thus steric limitations can occur, even with monomeric, homogeneous catalysts. 

Electrophilic and nucleophilic reactions of 2-(2-thienyl)thieno[2,3-cf pyrimidine (346), prepared as shown in Scheme 99, permits a conclusion concerning the reactivity compared with that of thiophene bearing an electron deficient substituent in position 2. Both nitration and bromination primarily occur in the thiophene moiety whereas lithium organic reagents (methyllithium, butyllithium) add at carbon atom 4 (77BSF676). Bromination of (324) yields the 5- (or 6-) bromo derivative (68CR(C)(267)697). 

M—1 sec-1) (Hart et al., 1964a). It has been pointed out that the replacement of a carbon atom of a double bond by a tertiary nitrogen atom increases the reactivity of the compound by two orders of magnitude (Anbar, 1965). This is true in the cases of pyrrole and imidazole, benzene and pyridine, as well as in the cases of thioazole and thiophene (k = 2-5 x 10° and 6-5 x 107, respectively) (Anbar andNeta, 1967a). 

The reactivity sequence furan > selenophene > thiophene > benzene has also been observed in the nucleophilic substitutions of the halogenonitro derivatives of these rings.21,22 This shows that the observed trend does not depend on the effectiveness of lone-pair conjugation of the heteroatoms NH, O, Se, and S and the 77-electron density at the carbon atoms. It is interesting to note that a good correlation is observed between molecular ionization potentials (determined from electron impact measurements) and reactivity data in electrophilic substitution, in that higher reactivities correspond to lower ionization potentials182 pyrrole furan < selenophene < thiophene benzene (see Table VII). This is expected in view of a... 

In Summary The donation of the lone electron pair on the heteroatom to the diene unit in pyrrole, furan, and thiophene makes the carbon atoms in these systems electron rich and therefore more susceptible to electrophilic aromatic substitution than the carbons in benzene. Electrophilic attack is frequently favored at C2, but substitution at C3 is also observed, depending on conditions, substrates, and electrophiles. Some rings can be opened by hydrolysis or by desulfurization (for thiophenes). The diene unit in furan is reactive enough to undergo Diels-Alder cycloadditions. Indole is a benzopyrrole containing a delocalized tt system. 

There are several systematic nuclear magnetic resonance studies of the interaction between the substituents and the protons and ring atoms of five-membered heterocycles. In some 2-substituted furans, thiophenes, selenophenes, and tellurophenes there is a linear correlation between the electronegativity of the chalcogen and several of the NMR parameters.28 As there also is a good correlation between the shifts of the corresponding protons and carbons in the four heterocycles, the shifts of unknown selenophene and tellurophene derivatives can be predicted when those of thiophene are known. This is of special interest for the tellurophene derivatives, since they are difficult to synthesize. In the selenophene series, where a representative set of substituents can be introduced in the 2- as well as in the 3-position, the correlation between the H and 13C shifts and the reactivity parameters according to Swain and Lupton s two-parameter equation... 

Although excellent yields of the unsaturated amides and urethans could be obtained, hydrolysis of the urethans gave poor yields of the aldehyde. The application of the Curtius degradation resulted in excellent yields of the various intermediates and a fair yield of the aldehyde. It appears that the presence of the heterocyclic moiety renders these aldehydes less stable than the corresponding aldehydes in the benzene series. Possibly the electron rich thiophene ring bestows a higher reactivity on the hydrogen atoms of the methylene carbon. 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of Af-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive to hydroxide addition at the carbonyl carbon than A-methylpyrrole-2-carbaldehyde (76JOC1952). Pyrrole-2-aldehydes fail to undergo Cannizzaro and benzoin reactions, which is attributed to mesomerism involving the ring nitrogen (see 366). They yield 2-hydroxymethylpyrroles (by NaBH4 reduction) and 2-methylpyrroles (Wolff-Kishner reduction). The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

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