Bromination of thiophenes

Fig. 13. Bromination of arenes with BTMA Bt3 Bromination of thiophene derivatives...

Halogenation can be run under milder conditions using more active quaternary ammonium polyhalides such as pyridinium tribromide. The reaction between thiophene and benzyltrimethylammonium tribromide in acetic acid-ZnCl2 provided 2,5-dibromothiophene [6]. Chloro- and iodo-substituted thiophene derivatives may be prepared in the same manner. In comparison, bromination of thiophene employing 2 equivalents of NBS in chloroform gave 2,5-dibromothiophene in 56% yield [7]. 

Tribromothiophene is reduced in good current yield to 3-bromothio-phene in 70% dioxane-30% water with sodium bromide as supporting electrolyte. At the anode the generated bromine may be used for bromination of thiophene 439 434 H. Lund, unpublished observation. 

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. 

Although bromination of thiophene in acetic acid gives good yields of 2-bromothiophene, quantitative yields are reported with dioxane dibromide (63AHC(l)l). Treatment of... 

In contrast with chlorination, bromination of thiophene always gives substitution products exclusively, and no addition products have been isolated under a variety of experimental conditions.82 Lauer83 first studied the kinetics of the reaction of thiophene with molecular bromine however, the reported value for the rate relative to benzene (2 x 104) is not reliable, because of the uncorrected value of k for bromination of benzene (for a discussion of this point, see Marino72). Later, the rate of bromination of thiophene relative to benzene in acetic acid was determined as 1.9 x 109, by comparing the times necessary to achieve 10% reaction in the bromination of thiophene and mesitylene, under the same conditions.72... 

In the presence of a large excess of bromide ions, the bromination of thiophene follows second-order kinetics,84 first-order in each reagent. The effects of the water content of the solvent, the ionic strength of the solution, the bromide ion concentration, and substituents in the aromatic substrate85 are the same in the bromination of... 

Bromination of thiophene derivatives by A-bromosuccinimide (NBS) in 50 50 (v/v) chloroform-acetic acid proceeds by an electrophilic rather than a radical mechanism.91 Many experimental facts favor such a hypothesis (i) only ring-substituted products are formed, with exclusion of addition or side-chain substitution (ii) the reaction is very selective, only a-substituted products are formed and (in) the... 

Fig. 6.30 Flow scheme of the rig for performing the bromination of thiophene continuously in a microstructured reactor. (Courtesy of the American Chemical Society [45].)...

Lowe, H., Mazanek, K., Bromination of thiophene in micro reactors, Lett. Org. Chem. 2(8) (2005) 767-779. 

A commercial synthesis of 2-bromothiophene was reported in the year 2014 (14PAT-2).The synthesis consists of oxidative bromination of thiophene with hydrogen bromide and hydrogen peroxide in dichloro-ethane at 40 °C. The method is amenable for large-scale production. Additionally, sequential one-pot syntheses of tri- and tetra-substituted thiophene and fluorescent push-pull thiophene acrylates involving (het)aryl dithioesters as thiocarbonyl precursors were reported (14MI-001). 

In contrast to toluene, the bromination of heteroaromatic compounds such as thiophene (Scheme 4.13) is very fast even at low temperatures ofO °C or below. Loeb and coworkers investigated the bromination of thiophene with regard to the control of multiple bromination employing a similar setup to that used for the bromination of toluene [26-28]. At a flxed bromine thiophene molar ratio of 1.0 the temperature was varied between 0 and 60 C, showing nearly no changes in the 1 1 ratio between one- and two-fold brominated products. The amount of three-fold substituted thiophene increased only slowly at elevated temperatures. At a fixed temperature of 50 °C, the authors varied systematically the molar ratio of bromine to thiophene from 1.0 to 5.0. The resultant product distribution obtained under conditions of complete thiophene conversion is shown in Figure 4.2. For 2,5-dibromothiophene (a relevant compound for the synthesis of OLE D materials), a selectivity of up to 80% could be achieved at a bromineithiophene molar ratio of 2.0. 

Scheme 4.13 Bromination of thiophene competition between single and multiple substitution.

Figure 4.2 Bromination of thiophene product distribution at 50°C. Taken from [26].

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