Reactions of Thiophene and Benzothiophene

Electrophilic substitution of the thiophene ring occurs predominately at the C2 position. As seen below, this is facilitated by the lone pairs on the sulfur atom. 

Addition at the C3 position of the thiophene is also possible, although unlikely unless the C2 position is already substituted. The electron-rich thiophene ring prefers electrophilic substitution at the C2 position because the intermediate has greater charge delocalization and, therefore, more stabilization in comparison to the less-favored C3 position. 

Monobromination of thiophene at the C2 position can be achieved in excellent yields by the slow addition of hydrobromic acid in the presence of hydrogen peroxide imder reduced temperatures.  

Bromination at both C2 and C5 is also possible with the addition of 

Lithiation of 3-methylthiophene and subsequent addition of an electrophile, in this case methyl iodide, produces a mixture of products at the C2 or C5 positions, with the 2,4-disubstituted thiophene predominating. However, a strong electron-withdrawing or sterically hindered C5-substituent will direct the formation of the C5 methylated thiophene to the more sterieally favorable position.  

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Ohta s group investigated the heteroaryl Heck reaction of thiophenes and benzothiophenes with aryl halides [127] and chloropyrazines [128]. Addition of the electrophiles invariably took place at C(2) as exemplified by the formation of arylbenzothiophene 156 from the reaction of benzothiophene and p-bromobenzaldehyde [127]. As expected, the heteroaryl Heck reaction of 2-thienylnitrile, an activated thiophene, with iodobenzene afforded the arylation product 157 [129],... 

Diels-Alder reactivity of thiophene and benzothiophene remains poorly understood. AMI semiempirical studies examining the activation of thiophene for this thermally allowed [4+2] cycloaddition process have shown that the usual synthesis approaches (use of highly reactive dienophiles, substitution on thiophene, increased reaction pressures) have only small effects on rate enhancement. However, use of the corresponding S-methylthiophenium salts, which have little aromaticity, should provide excellent activation for Diels-Alder reactions of thiophenes even with poor dienophiles such as ethylene <95JHC483>. This AMI approach has been applied to examine Diels-Alder reactions of benzo[6] and benzo[c]thiophenes the theoretical data agree with experimental results <95JCS(P1)1217>. 

Homogeneous model complexes shed light on the reactivity of thiophene and benzothiophene. Thiophene is known to coordinate to metals in if- to -fashion, as in (21-XXIV) to (21-XXVII). The rf-S and rf-C,C structures are believed to act as immediate precursors to C—H and C—S addition reactions. This was confirmed spectroscopically for the reaction of (pp3)Ru(N2) with thiophene ... 

During the adsorption and desorption of thiophene on HZSM5 zeolites, reversible surface reactions of thiophene to unsaturated thiol-like species were found even at room temperature. Condensation reactions of thiophene to benzothiophene were observed over HZSM5 only but not over the NaZSMS samples [3]. Cleavage of the C-S bond and formation of SH surface groups were observed during thiophene adsorption on HY zeolites [4]. 

The group of Jones has described the desulfurization of thiophene and benzothiophene using [Ir2(Cp )2(H)2(p-H)] with excess TBE (t-butylethylene) or [lr(Cl)(Cp )(H)]2 in the presence of H2 [53, 106]. The reactions evenmally afford diiridium complexes with sulfide and q q -butadiene bridges and seem to proceed via two consecutive carbon-sulfur bond cleavages that require more than one metal center and the ability to form bridging thiolate intermediates (Scheme 21) [107]. 

The arene substrates are not limited to simple benzene derivatives. A variety of het-eroarenes can also participate in alkene arylations to generate the desired coupling products. Stoichiometric oxidative coupling of aromatic heterocycles such as furan, thiophene, selenophene, A-methylpyrrole, benzofiiran and benzothiophene with a variety of alkenes, including acrylonitrile, styrene and methyl acrylate, have been extensively studied by Fu-jiwara and coworkers [8]. Furan, thiophene, selenophene and A-methylpyrrole are easily alkenylated with alkenes to give 2-alkenylated and 2,5-dialkenylated heterocycles in relatively low yields (3 6%) [8a], while the reactions of benzofuran and benzothiophene with alkenes produced a mixture of 2- and 3-alkenylated products [8b]. 

Several more complex reactions such as the catalytic reforming of heptanes on Pt/Re/alumina were dealt with in terms of sets of rate equations of the Hougen-Watson type by Van Trimpont et al. [1986]. The hydrogenolysis of thiophene and benzothiophene on Co/Mo/alumina was studied along the same lines by Van Parijs et al. [1986a, b] and is also discussed in Examples 2.6.4.A and 2.7.2.2.A. 

Thiophenes continue to play a major role in commercial applications as well as basic research. In addition to its aromatic properties that make it a useful replacement for benzene in small molecule syntheses, thiophene is a key element in superconductors, photochemical switches and polymers. The presence of sulfur-containing components (especially thiophene and benzothiophene) in crude petroleum requires development of new catalysts to promote their removal (hydrodesulfurization, HDS) at refineries. Interspersed with these commercial applications, basic research on thiophene has continued to study its role in electrocyclic reactions, newer routes for its formation and substitution and new derivatives of therapeutic potential. New reports of selenophenes and tellurophenes continue to be modest in number. 

Oxidation of thiophene and its derivatives was studied using hydrogen peroxide (H2O2), t-butyl-hydroperoxide and Ti-Beta redox molecular sieve as selective oxidation catalysts. A new reaction pathway was discovered and investigated using C-13 NMR, GC, GC-MS, HPLC, ion chromatography, and XANES. The thiophene oxidized to thiophene-sesquioxide [3a,4,7,7a-tetrahydro-4,7-epithiobenzo[b]-thiophene 1,1.8-trioxide] and the sesquioxide oxidized mostly to sulfate. 2-Methyl-thiophene and 2,5 dimethylthiophene also oxidized to sulfate and sulfone products. The Benzothiophene oxidation product was sulfone. This proposed new reaction pathway is different from prior literature, which reported the formation of thiophene 1,1-dioxide (sulfone ) as a stable oxidation product... 

The oxidation of thiophene and its derivatives with H202 was studied using a Ti-Beta molecular sieve. The oxidation product is very dependent from the aromaticity of model compounds. The thiophene oxidation product was mostly sulfates and the benzothiophene oxidation product was benzothiophene sulfone. Oxidation of mono and di-alkyl thiophenes also produced sulfates and sulfones. The diffusivity and aromaticity of the relevant sulfur compounds, intermediates and stable product, as well as the proposed new mechanism of oxidation will be discussed. This proposed new reaction pathway is different from current literature, which reports the formation of sulfones as a stable oxidation product. 

In describing catalytic activities and selectivities and the inhibition phenomenon, we will use a common format, where possible, which is based on a common reaction pathway scheme as outlined in Scheme 1. In contrast to the simple one- and two-ring sulfur species from which direct sulfur extrusion is rather facile, in the HDS of multiring aromatic sulfur compounds such as dibenzothiophene derivatives, the observed products are often produced via more than one reaction pathway. We will not discuss the pathways that are specific for thiophene and benzothiophene as this is well represented in the literature (7, 5, 8, 9) and, in any event, they are not pertinent to the reaction pathways involved in deep HDS processes whereby all of the highly reactive sulfur compounds have already been completely converted. 

As discussed in Section III, when the sulfur content is lowered from 0.20 to 0.05%, the chemistry of HDS of gas oils is essentially the chemistry of alkyl-substituted dibenzothiophenes. Though gas oils initially contain mostly alkyl-substituted benzothiophenes, these are completely removed by the time 0.20% S is achieved. Thus, this review will deal predominantly with the reaction pathways involved in the HDS of alkyl-substituted dibenzothiophenes. There are many excellent reviews on reaction pathways of the more reactive sulfur species such as thiophenes and benzothiophenes (2, 5, 8, 23, 24), and the reader is referred to those reviews for information on the reaction pathways and mechanisms of HDS for the more reactive... 

The purpose of this section is to call attention to the best laboratory synthetic methods of producing thiophene and benzothiophene derivatives in yields satisfactory for utility. Since methods of constructing the parent ring systems have been surveyed earlier in the chapter, and the introduction of substituents on the parent ring systems has been discussed in Chapter 3.14, specific examples of the synthetic reactions have been discussed earlier. Industrial processes for the parent ring systems, thiophene and benzothiophene, have been adequately covered <52HC(3)i, 54HC(7)l). 

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). 

The reactions of a series of arynes from aromatic anhydrides with thiophene and benzothiophene at 690° revealed some processes not as clearly evident with other reagents. 

The major products from the reaction of arynes with thiophene and benzothiophene by addition and insertion are shown in Table 11. Benzyne from phthalic anhydride reacted with thiophene at 690° to give naphthalene and benzothiophene by 1,4-addition and loss of sulfur, and by 1,2-addition and loss of acetylene, respectively, as well as phenyl-thiophene by insertion (Fields and Meyerson, 1966d, 1967e) (Scheme 19). The ratio of naphthalene to benzothiophene was about 9 1, nearly the same preference for 1,4-over 1,2-addition as was inferred from the reaction of benzyne with dichlorobenzenes and pyridine at the same temperature, and again reflects the strong tendency of benzyne to act as a dienophile. 

As benzothiophene was a product of both the reaction of benzyne with thiophene and the pyrolysis of thiophene alone (Fields and Meyerson, 1966d), we investigated the reaction of benzyne with benzothiophene. Pyrolysis of a mixture of phthalic anhydride and benzothiophene gave the products shown in Table 11. Anthracene and dibenzothiophene probably arose via 1,2-, and phenanthrene via 1,4-addition to the thiophene ring ... 

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