Reactivity of Thienothiophenes

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

Dean and E. V. Whitehead in 6th World Petroleum Congress, 1963, Verein zur Forderung des 6. Welt-Erddl-Kongresses, Hamburg W. Germany, Sect. 5, Paper 9, p. 261. 1964. 

Thieno[3,4-6]thiophene (3) possesses three plausible sites of attack, positions 2,4, and 6. However, consideration of resonance structures in-dcates that electrophilic substitution should occur at positions 4 or 6 rather than at 2. 

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.  

Lithiation by hydrogen abstraction by /i-butyllithium in the isomeric thienothiophenes 1-3 proceeds by a different mechanism, but again results in 2-substitution in thienothiophenes 1 and and 4- and 

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Recently Bugge studied the reactivities of thienothiophenes 1 and 2 and thiophene by the competitive method, utilizing SnCl4-catalyzed acetylation with acetic anhydride, Vilsmeier formylation and chlorination with iV-chlorosuccinimide. Thienothiophenes 1 and 2 are always more reactive than thiophene. In acetylation the reactivities of 1 and 2 are similar, while in formylation and chlorination thienothiophene 2 is somewhat more reactive than isomer 1 (Table V). 

The reactions and reactivities of thienothiophenes (3) and (7) have been studied in detail. Isomer (8) has been studied, but in lesser detail than (3) and (7) <76AHC(19)123). Subsequently, work on the reactivities of the selenium analogs (4) and (29) was reported... 

Theoretical Studies and Physical Properties.—Quantum chemical calculations on the reactivity of thienothiophens have been carried out. " The e.s.r. spectra of the radical anions of carbonyl, nitro, and cyano derivatives of the two [b]-fused thiophens have been studied. The proton chemical shifts of 2-substituted thieno[2,3-b]thiophens have been correlated with the two-parameter equation of Swain and Lupton. " ... 

AC2O/S11CI4), and nitration [Cu(N03)2] of thienothiophenes 1 and 2. He recently also studied the effect of the a-substitution (with halogen, CH3, SCHj, CN, NO2, COCH3, and COOH groups) on the chemical shifts of protons. He observed a good correlation between the shifts, reactivity constants, F (the field effect), and R (the resonance effect). ... 

Chromatographic separation clarified the peculiarities of acetonyl-thiothiophene cyclization in the presence of duminum chloride. " Gas-liquid chromatography also allowed quantitative estimates of the relative reactivities of thiophene and the isomeric thienothiophenes 1 and... 

The first quantitative data comparing the reactivities of the a-positions in isomeric thienothiophenes 1 and 2 with that of thiophene appeared in 1970. The kinetics of electrophilic dedeuteration of the... 

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, ... 

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... 

From n -electron calculations, the following order of reactivity of the thienothiophenes 1-3 in free-radical substitution reactions was predicted thieno[3,4-b]thiophene (3) > thiophene > thieno[3,2-M-thiophene (2) > thieno[2,3-6]thiophene (1), the most reactive positions being 2 and S in tiiienothiophenes 1 and 2, and 4 and 6 in thienothiophene 3. ... 

Calculations have been carried out to estimate the relative reactivities of the isomeric thienothiophenes in comparison with thiophene or naphthalene. The localization energy is expected to be the most adequate index of reactivity (76AHC(19)123). 

Hiickel calculations of localization energies ((3CS = 0.6, as = ac) give the positional orders as 2 (thiophene) > 2 [3,2-6] > 2 [2,3-6] > 3 [2,3-6] > 3 [3,2-6] > 3 (thiophene).[82JCS(P2)295]. The reactivity of the 2-position of thiophene is clearly predicted incorrectly, and the order for the 2-positions of the thienothiophenes reflects that found for chlorination and formylation, which have transition states nearer to the Wheland intermediate. (Localization energy calculations assume, of course, that... 

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