Thienothiophenes reactivity

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... 

A. Isotope Exchange of Deuterated Thienothiophenes Quantum-Chemical Reactivity Calculations... 

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... 

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). 

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. 

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. ... 

However, experimental studies of the effect upon thiophene or thienothiophenes 1 and 2 of phenyl radicals obtained by thermal decomposition of iV-nitrosoacetanilide, or from aniline and amyl nitrite, demonstrated a somewhat different experimental order of reactivity thieno[3,2-6]thiophene (2) > thiophene > thieno[2,3-6]thiophene (1). It was also found that the phenyl radical preferentially attacks position 2... 

The parent nonclassical thienothiophene (9) is unknown although alkyl- and ester-substituted derivatives (10) and (11) have been generated in solution and found to be highly reactive intermediates. The tetraphenyl derivative (6) of thieno[3,4-c]thiophene, on the other hand, is stable indefinitely in the solid state, although it is destroyed in solution by light and air, but not by light alone. 

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... 

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). 

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). 

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). 

The free radical phenylation experiments indicated that the order of reactivity is (3) > thiophene > (7). Calculations on all the three classical thienothiophenes, however, had predicted a different order of reactivity, viz. (8) > thiophene > (3) > (7). The most reactive positions were also expected to be the a-positions (76AHC(19)123). 

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