Thienothiophenes electrophilic substitution

Bugge calculated relative rates of various electrophilic substitutions with respect to the /3-position in thiophene (Table VI). The following order of decreasing reactivity applied a-position in thienothiophene 2 a-position in thienothiophene 1 > a-position in thiophene > position in thienothiophene 1 > /3-position in thienothiophene 2 > /3-position in thiophene. 

Semiempirical methods of calculation with consideration of all valence electrons have been used only recently but already have given results on the reactivities of some aromatic and heteroaromatic com-pounds. " Thus, to analyze the reactivities of thiophene and the isomeric thienothiophenes 1-3 to electrophilic substitution, the semiempirical SCF LCAO MO method CNDO/2 was used, taking into account all valence electrons.The 3s, 3p, and 3d orbitals have been taken into account for the sulfur atom. Tlie reactivities were estimated from the difference between bond energies of the initial and the protonated molecule (in a complex). ... 

The reactivities of isomeric thienothiophenes calculated in n -electron approximation by the PPP method, and those calculated considering all valence electrons, show reasonable agreement. It should be noted, however, that the choice of parameters in PPP calculations is somewhat arbitrary, especially for heavy atoms (e.g., sulfur). This may lead to a discrepancy between theoretical (in 7r-electron approximation) and experimental estimation of reactivities. For example, Clark applied the semiempirical method PPP SCF MO to calculate the reactivities of different positions in thienothiophenes 1—3, thiophene, and naphthalene from the localization energy values and found the following order of decreasing reactivity for electrophilic substitution thieno[3,4-b]-thiophene (3) > thieno[2,3-Z>]thiophene (I) > thieno [3,2-b]thiophene... 

Oxidation of acetyl- and acetylnitro-substituted thienothiophenes 1 and 2 with ferricyanide or hypoiodite to the corresponding acids was used primarily to confirm the site of electrophilic substitution at position 2 in the thienothiophenes. " Permanganate degrades the thieno[3,2-A]-thiophene (2) ring system, while potassium hypobromite produced bromo derivatives of thieno[2,3-6]thiophene-2-carboxylic acid. ... 

As in other electrophilic substitutions, mercuration of thienothiophenes (7) and (3) leads to a-substituted derivatives (102) and (103). When the a-positions are blocked as in (73), /3-mercuration occurs leading to the formation of the mercury derivative (104). In the early investigations on the classical thienothiophenes, organomercury derivatives were used for characterization purposes. Although the mercury function in (102)-(104) can be replaced by other electrophiles, at the present time the procedure has no practical significance <76AHC(19)123). 

It becomes evident that the a-positions in the thienothiophenes (3), (7) and (8) are the most reactive sites in the molecule, from their behavior in electrophilic substitution reactions. This behavior parallels that of thiophene, and is not unexpected when one considers the resonance forms in (3), (7) and (8 Scheme 31). 

Although thienothiophene (8) should be vulnerable to electrophilic substitution at C-2, C-4 and C-6, on the basis of the resonance structures it becomes clear why substitution occurs at C-4 and C-6 rather than at C-2. 

Both thienothiophenes (3) and (7) were subjected to competitive electrophilic substitution reactions with thiophene. The fused heterocycles were always more reactive than thiophene in acetylation, Vilsmeier formylation and chlorination with NCS. While acetylation of both (3) and (7) occurrred at a comparable rate, formylation and chlorination occurred faster in the [3,2-6]-fused isomer (3) than in the [2,3-6] isomer (7). 

Electrophilic substitution in thieno[2,3-6] and [3,2-b]thiophene systems is expected to proceed similarly to that in thiophene (see, e.g., Gronowitz219 and Marino216), a substitution occurring at position 2. Schomaker and Pauling217 were the first to discuss this effect in the case of thiophene. Challenger and Fishwick26 came to a similar conclusion about thienothiophene 1 on the basis of the possible resonance forms. 

Recently computed CNDO/2 localization energies of electrophilic substitution for thiophen and the thienothiophens (51) and (53) (protonated o--type complexes without geometry optimization) have provided only a fair correlation with experimental rate constants. The values for localization energies predicted by the CNDO/2 method do not appear to be an improvement over those predicted by the PPP method. 

The experimental data on the isomeric thienothiophenes 1—3 support these predictions. Electrophilic attack on thienothiophenes 1 and 2 results in 2-substituted compounds (see refs. 20, 21, 25, 28, 41, 218, 219). The second electrophilic substituent enters position 5. Tliieno-thiophene 3 is attacked at positions 6 and 4 to give, for example, 4- and 6-formylthieno[3,4-6]thiophenes on formylation. ... 

Aromatic substitution reactions are often complicated and multistep processes. A correlation, however, in many cases can be found between the charged attacking species and the electron density distribution in the molecule attacked during electrophilic and nucleoph c substitution. No such correlation is expected in radical substitution where the attacking particles are neutral, rather a correlation between the reactivities of separate bonds and a free valency index of the bond order. This allows the prediction of the most reactive bonds. Such an approach has been used by researchers who applied quantum calculations to estimate the reactivities of the isomeric thienothiophenes and to compare them with thiophene or naphthalene. " Until recently quantum methods for studying reactivities of aromatics and heteroaromatics were developed mainly in the r-electron approximation (see, for example, Streitwieser and Zahradnik ). The M orbitals of a sulfur atom were shown not to contribute substantially to calculations of dipole moments, polarographic reduction potentials, spin-density distribution, ... 

Substitution Reactions.—In contrast to benzo[6]thiophen, the thienothiophens undergo electrophilic aromatic substitution predominantly in the... 

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