Nitration of thiophene

Nitro derivatives of thiophene are of considerable interest some are biologically active others are useful synthetic intermediates for chemical modifications and for the synthesis of biologically active compounds. 

Other useful thiophene-nitrating reagents include copper(ll) nitrate in acetic anhydride and aluminium nitrate in acetic anhydride [128, 129]. Nitration of substituted thiophenes is subject to the usual mesomeric and inductive effects of the substituents [130]. Nitration can also take place at already substituted positions, replacing bromine or iodine (see, e.g. [131]). The nitration of 

5- dimethylthiophene using copper(II) nitrate in acetic anhydride led to 

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Nitration. It is difficult to control nitration of thiophene, which yields 2-nitrothiophene [609-40-9]. The strongly electropbilic nitronium ion leads to significant yields (12—15%) of 3-isomer. A preferred procedure is the slow addition of thiophene to an anhydrous mixture of nitric acid, acetic acid, and acetic anhydride. 

Nitration of thiophene with cupric nitrate in acetic anhydride or acetic acid is considered to be milder than nitric acid in the same solvents and has been used successfully with thiophene derivatives which decomposed on conventional nitration/ ... 

It is thus apparent that the selectivity of a reagent toward thiophene and benzene can differ appreciably, and this difference in selectivity is also strongly noticeable in the proportions of 2- and 3-isomers formed. Although in certain reactions no 3-isomer has been detected, appreciable amounts have been found in other reactions. Thus 0.3% of the 3-isomer has been found in the chlorination of thiophene.- Earlier results indicated that 5-10% 3-nitrothiophene is formed in the nitration of thiophene and a recent gas-chromatographic analysis by Ostman shows that the mononitrothiophene fraction contains as much as 16% of the 3-isomer. It appears that gas-chromatographic analysis should be very useful for the detection of small amounts of 3-isomers in other substitution reactions. However, from routine analyses of IR spectra, it appears to the present author that the amount of 3-isomers formed in acylation, formylation, and bromina-tion of thiophene are certainly less than a few per cent. 

Direct nitration of thiophene, using a mild nitrating system at low temperature, gives 2-nitrothiophene in excellent yield. Acetyl nitrate, benzoyl nitrate or copper(I) nitrate in acetic anhydride or acetic acid is commonly used, and only traces of 3-nitrothiophene and 2,5-dinitrothiophene are formed. Slow addition of thiophene dissolved in acetic anhydride to a solution of nitric acid in glacial acetic acid, maintaining the temperature at 10°C, is reported to be the optimum procedure (Section 3.14.2.4.8). 

Many quantitative and semiquantitative studies on the nitration of thiophene have been carried out113,121-123 and the rate of nitration of thiophene relative to benzene has been determined under different experimental conditions. However, these relative rate values probably do not reflect the true relative reactivities, for the reasons stated above. 

Ostman122 has determined the kinetic isotope effect in the nitration of thiophene by benzoyl nitrate in acetonitrile the observed effect ( T/fcH= 1.14 + 0.10) is opposite to that expected for a primary isotope effect. It seems likely that it is a secondary a-isotope effect, ascribable to a rate-determining nature of the bond-formation step and similar to that observed by Olah et al. in the nitration of benzene derivatives with nitronium fluoroborate in tetramethylenesulfone.124... 

Nitration of thiophene 2-carbaldehyde has been reported to give a mixture of all three mononitro isomers in the ratio 3-nitro (62%), 4-nitro (15%), and 5-nitro (23%). This mixture could not be condensed with 2-acetylpyridine in NaOH instead, the thiophene ring was ruptured <2006S1295>. 

Nitration of thiophene needs to be condncted in the absence of nitrous acid, which can lead to an explosive reaction the nse of acetyl nitrate or nitronium tetraflnoroborate is satisfactory. The major 2-nitro-prodnct is accompanied by approximately 10% of the 3-isomer. ° Further nitration of either 2- or 3-nitrothiophenes also leads to mixtnres eqnal amounts of 2,4- and 2,5-dinitrothiophenes from the 2-isomer, and mainly... 

Many quantitative and semiquantitative studies on the nitration of thiophene have been carried out 121-123 nitration... 

Ostman has determined the kinetic isotope effect in the nitration of thiophene by benzoyl nitrate in acetonitrile the observed effect 1.14 0.10) is opposite to that expected for a primary... 

Nitration of thiophenes has been exhaustively reviewed <86HC(44/2)523, 90AHC(47)87>. Very few new results have been reported in this area since the mid-1980s. 

Scheme 84 Use of HNO3 with AC2O in AcOH for nitration of thiophene [127]...

Early attempts to nitrate thiophene and to reduce a nitro-product, in analogy with benzene chemistry, were unsuccessful until the conditions for nitration of thiophene were found. Eventually, rather special conditions were developed thiophene vapour mixed with air was passed for several hours through fuming nitric acid. After work-up, mononitrothiophene and a dinitrothiophene were isolated [125], Later it became clear that the failure in thiophene nitration with nitric acid is due to the presence of nitrous acid that led to the formation of nitrosothiophene, which is prone to decomposition [ 126]. A mixture of nitric acid with acetic anhydride in glacial acetic acid can mononitrate thiophene very effectively (Scheme 84) [127]. 

Cerium(lll) ammonium nitrate (CAN) in acetic anhydride is also an efficient nitrating reagent for aromatic compounds [135]. The nitration of thiophene by CAN gave a mixture of 2-nitro- (58%) and 3-nitrothiophene (12%) (Scheme 86) [134]. 

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