Electrophilic substitution of thiophenes

Thiophene undergoes electrophilie substitution resulting in two possible isomers, e.g., for nitration. 

Aceording to Frontier Molecular Orbital (FMO) theory, thiophene s most reactive site can be identified by examining the shape of its highest-occupied molecular orbital (HOMO). Which atoms contribute to thiophene s HOMO Which atom(s) contributes the most Which nitration product should form preferentially  

Another way to assess thiophene s reactivity is to compare the intermediate ions formed by addition of N02. Examine the structures, charge distributions and electrostatic potential maps of thiophene+nitronium at C2 and thiophene+nitronium at C3. Draw all of the resonance contributors needed to describe these structures. Which, if either, better delocalizes the positive charge Compare the energies of the two intermediates. Which product should form preferentially if the reaction is under kinetic control Are these results consistent with FMO theory  

Does the fact that thiophene reacts similarly to benzene mean that it is aromatic One way to tell is to calculate first and second hydrogenation energies of thiophene, leading to dihydrothiophene and tetrahydrothiophene, respectively. (The energy of hydrogen is provided at right.) 

Whereas the initial hydrogenation both breaks a K bond, as well as destroys any aromatic stabilization, the second hydrogenation only breaks the k bond. Is this difference large as in benzene (see discussion at right), or is it much smaller or neglible Is thiophene aromatic  

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Electrophilic substitution of thiophene occurs largely at the 2-position and the reactivity of the ring is greater than that of benzene. 3-Substituted derivatives are generally prepared by indirect means or through ring cyclization reactions. 

The electrophilic substitution of thiophene is much easier than that of benzene thus, thiophene is protonated in aqueous sulphuric acid about 10 times more rapidly than benzene, and it is brominated by molecular bromine in acetic acid about 10 times more rapidly than benzene. Benzene in turn is between 10 and lo times more reactive than an uncharged pyridine ring to electrophilic substitution. 

This and other older methods, which have been reviewed previously (21, 22), have been largely superceded in the laboratory by more controlled, selective reactions, starting from suitable thiophene precursors. We shall discuss two major reactions which can be used for the preparation of alkylthiophenes electrophilic substitution of thiophenes and the formation and reactions of lithiated thiophenes. For further details and other aspects of thiophene chemistry the reader is referred to previous reviews (21, 22) and references cited therein. Accounts of yearly developments in thiophene chemistry can also be found in the relevant Royal Society of Chemistry publications. 

Electrophilic Substitution of Thiophenes. Electrophilic substitution involves the reaction of electron deficient species, so-called electrophiles (E+), with suitable substrates, in this case thiophene or alkylthiophenes, to give a 2-substituted thiophene (Figure 2). 

Figure 3. Consideration of Wheland intermediates for electrophilic substitution of thiophene at (i) C-2, (ii) C-3.

Bromination. Another useful example of electrophilic substitution of thiophene and alkylthiophenes is that of bromination. Thus, thiophene itself undergoes electrophilic substitution in the presence of bromine. The reaction proceeds systematically from 2-bromothiophene, to 2,5-dibromothiophene, to 2,3,5-tribromothiophene and finally to tetrabromothiophene (29, 30). These brominated thiophenes exhibit sufficiently different physical properties to allow their ready purification. A more controlled method, especially for mono-... 

Alkylthiophene preparation acylation, 401-407 bromination, 407,408/ electrophilic substitution of thiophenes,... 

Isomer Distributions and a j8 Reactivity Ratios in Electrophilic Substitutions of Thiophene ... 

Table XXIV provides a summary of the p values for the electrophilic substitutions of thiophene derivatives when available, the p values for the corresponding reactions of benzene derivatives are also recorded for comparison.

Desulfurization of thiophenes 88MI17 89CRV459 90MI13. Electrochemical functionalization of halothiophenes 90S369. Electrophilic substitution of thiophenes 86HC(44,2)1. 

Electrophilic substitution of thiophene has been expertly reviewed by Taylor <86HC(44/2)l>. In addition, a whole monograph has b n devoted to the compilation and analysis of quantitative data on electrophilic substitution of heterocycles <90AHC(47)87>. The highlights from the conclusions reached in the section on thiophene are presented below. 

Isomer distributions have been determined for several electrophilic substitutions of thiophen, such as bromination by Bra and Br+, chlorination by tin tetrachloride, or iodine-catalysed acetylation by acetic anhydride, trifluoroacetylation, and Vilsmeyer formylation. The a. ratios vary from 100 to over 1000, according to the selectivity of the electrophilic agent. The results obtained, together with other data from the literature, permit a test of the applicability of linear free-energy treatments to electrophilic substitution at the a- and j8-positions of thiophen. Plots of log (Xf and log jSf against p for nine reactions were linear, and from the slopes values of = — 0.79 and 0)3+ = — 0.52 were obtained. Serious deviations were observed for mercuration and protodemercuration, while nitration and protodeboronation were not taken into account, as deviation could be expected for various reasons. The linearity was taken as evidence... 

Scheme 2 Electrophilic substitution of thiophene - preferred at an a-position...

Scheme 1 The possible ways (a or b) for electrophilic substitution of thiophene [2]...

Taylor R (1985) Electrophilic substitution of thiophene and its derivatives. In Gronowitz S, Weissberger A, Taylor EC (eds) Thiophene and its derivatives, part 2. The chemistry of heterocyclic compounds, vol 44. Wiley, New York/London/Sydney/Toronto... 

Two papers dealing with HMO calculations of the chemical reactivity of substituted thiophens should be noted one on the acid-catalysed hydrogen exchange" and the other on the transmission of substituent effects across the thiophen ring" Gol dfarb et al." have studied another problem in chemical reactivity electrophilic substitution of thiophen-2-carbaldehyde occurs in the 5-position but at the 4-position when this compound is protonated, and substitution in protonated 2-amino-thiophens occurs at the 5-position despite the m-directing property of the ammonium group. They found the chemical reactivity to be related to the CNDO/2 valence-electron densities." ... 

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