2,3,5-substituted thiophenes

The y-CH modes arising from out-of-plane C H deformations should be characteristic of the substitution pattern and the observed frequencies are summarized in Table 23. For 2-substituted compounds these may be assigned as (31), (32) and (33). Additional characteristic bands for 2-substituted thiophenes are observed at 870-840m and 740-690s cm (67RTC37). ... 

Gronowitz et al. have discussed the effects of substituents on chemical reactivity and on ultraviolet (XJV), infrared (IR), and nuclear magnetic resonance (NMR) spectra in terms of simple resonance theory,They assume resonance structures (1-5) to contribute to a —I—M (Ingold s terminology) 2-substituted thiophene, resonance forms (6-10) to the structure of a drI-fM 2-substituted thiophene, forms (11-16) to a —I—M 3-substituted thiophene, and forms (17-22) to a I -M 3-substituted thiophene. 

Physical and chemical evidence supporting the theory mentioned in the foregoing will be given in the appropriate sections. Some predic-. tions may be mentioned here. From resonance structures (2, 3, 7, 8) it is inferred that the substituent effect in 2-substituted thiophenes should be parallel to that in the corresponding benzenes, the 3- and 5-positions may be considered as ortho and para positions and the 4-position as a meta position. It is, however, obvious that the effect of a —M- and a d-M-substituent are not simply reversed, as reso-... 

Substit- uent CHiaracter 2-Substituted thiophenes 3-Substituted thiophenes ... 

In the benzene series, an approximately linear relationship has been obtained between the chemical shifts of the para-hydrogen in substituted benzenes and Hammett s a-values of the substituents. Attempts have been made, especially by Taft, ° to use the chemical shifts as a quantitative characteristic of the substituent. It is more difficult to correlate the chemical shifts of thiophenes with chemical reactivity data since few quantitative chemical data are available (cf. Section VI,A). Comparing the chemical shifts of the 5-hydrogen in 2-substituted thiophenes and the parahydrogens in substituted benzenes, it is evident that although —I—M-substituents cause similar shifts, large differences are obtained for -j-M-substituents indicating that such substituents may have different effects on the reactivity of the two aromatic systems in question. Differences also... 

The characteristic bands in the IR spectra of thiophenes have been recorded. " 2-Substituted thiophenes show ring-stretching frequences at 1537-1509, 1444-1402, and 1365-1339 cm" which have been assigned to characteristic modes of vibration. The hydrogen in-plane deformation bands occur at 1086-1077 and at 1053-1031 cm. The... 

The UV spectra of —I—M 2-substituted thiophenes show two almost overlapping high-intensity bands both of which are displaced, with increasing conjugating power of the substituent, toward longer wavelengths. The extinction increases in the same order as in the... 

Thiophenes substituted with groups such as alkyl, halogens, OCH3, and SCH3 show small but characteristic differences between 2- and 3-substituted compounds. In these cases, however, it is the 2-isomer which shows the less complex spectrum. Thus, 2-substituted alkylthio-phenes and halothiophenes show a single band with greater extinction than the 3-isomers whose spectra exhibit two peaks in a broadened absorption band. These differences are also present in the spectra of 2,5- and 3,4-dihalosubstituted compounds. In 2-substituted thiophenes, the intensity of the band varies inversely as the electronega-... 

Most 2-substituted thiophenes are easily available through direct aromatic substitution, followed by suitable transformations of the groups so introduced. Some recent developments will be briefly outlined in this section. 

It can be seen from resonance structures (2) to (4) that a — I — M-substituent deactivates the 3- and 5-position most strongly in electrophilic substitution. If this deactivation of the 5-position is strong enough to overcome the activating effects of the sulfur in the 5-position, substitution will be directed to the 4-position to an increasing extent. Tirouflet and Fournari studied the nitration of 2-substituted thiophenes of this type. The analysis was carried out polarographically, and the percentage of 4-isomer was as follows ... 

The ease with which electrophilic substitution occurs in position 4 in thiophenes containing a —I—M-substituent in position 3, if the reactive a-positions are blocked with halogens or methyl groups, in contrast to the difiiculty of achieving such substitution in the 3-position of a —I—M 2-substituted thiophene was noticed already by Steinkopf et They easily dinitrated and disulfonated 2,5-di-... 

Wynberg has discovered the most interesting reaction in the photochemical reactivity of thienyl derivatives. The irradiation of 2-substituted thiophenes gave the corresponding 3-substituted derivatives (Scheme 17). 

The mercuration of 2-substituted thiophenes by mercuric acetate at temperatures between 16.9 and 50.0 °C has been shown to be second-order over the first 20 % of reaction449. The activation energies for thiophen and its 2-acetyl, 2-methyl,... 

Butyllithium effects C-2 lithiation, and the lithium derivative can then be reacted with electrophiles (this is a good way to synthesize a wide variety of 2-substituted thiophenes) (Scheme 6.36). 

A general scheme of possibilities for 2-substituted thiophenes, X being in practice NHR, OH or SH, is given in equation (13). The same is shown for 3-substituted derivatives in equation (14). 

In 2-substituted thiophenes these bands are found in the ranges 1537-1509, 1444-1402, 1365-1339 and 1258-1220 cm-1, along with hydrogen in-plane absorption at 1086-1077 and 1053-1031 cm "1, and hydrogen out-of-plane absorption at 938-905 and 863-841 cm-1 as well as a ring breathing mode at 839-790 cm-1 (59JCS3500). 

Recent efforts in the area of Friedel-Crafts alkylations have focused on the direct introduction of alkyl groups bearing functionalities, and on intramolecular alkylative cycliz-ations. The cyclization of the 2-substituted thiophene (55) to (56) has been achieved in 65% yield (80JOC3159). Similarly, the 3-substituted thiophene (57) has been cyclized to the isomeric (58). In both cases, detosylation of the product was achieved by treatment with diisobutylaluminum hydride (DIBAL). An elegant bis-cyclization of the diene (59) to the octahydrodibenzothiophene (60) has been reported (70CJC2587). 

For the trifluoroacetylation of 2-substituted thiophenes, furans, and pyrroles in C2H4C12, 75°, the p values are —7.4, —10.3, and ca. —4.5, respectively.259 The value for substituted benzenes is not known. In the gas phase ionization of substituted furans, thiophenes, selenophenes, and pyrroles,264 a reaction proceeding through a positively charged molecular ion taken to be analogous to the Wheland intermediate for electrophilic substitution, the p values are reported to be —20.2, —16.5,... 

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). 

Carbenoid insertion into the C-S bond of 2-substituted thiophenes competes with cyclopropanation at the C=C bonds. Formation of the ylide 402 and hence a thiopyran by way of a Stevens rearrangement is the dominant pathway for 2-(methylthio)thiophene, but is less significant for the 2-methyl and 2-trimethylsilyl derivatives (Scheme 115) <1998T15499>. 

Isomer Distributions in Nitration of Negatively 2-Substituted Thiophenes... 

The relative rates of bromination of some 2-substituted thiophenes (R = H, CH3, Cl, Br, I, C02H, C02Et) by molecular bromine in anhydrous acetic acid have been determined by the author,85 comparing the times necessary to achieve 10% reaction. All the thiophenes examined gave the 5-bromo derivative on substitution, without appreciable formation of any other isomer. Only 2-iodothiophene... 

Fig. 6. Plot of log kjko vs ap+ constants for the bromination of 2-substituted thiophenes in acetic acid see Marino.85...

Later, Butler and Hendry294 repeated this work, measuring the rates of bromination of some 2-substituted thiophenes (the same derivatives used by Marino85 plus 2-ethyl, 2-Z-butyl, and 2-phenyl) in 85% aqueous acetic acid and in the presence of lithium bromide. The p value obtained was identical (—10.0), showing that it is not affected at all by passing from anhydrous to aqueous acetic acid. 

In Fig. 7 an analogous plot for the uncatalyzed chlorination of 2-substituted thiophenes in anhydrous acetic acid is reported. The... 

Cation 6 adds to furan, pyrrole, thiophene and some of their 2,4-dimethyl derivatives bearing a free a-position, in MeCN as solvent. Furan is the least reactive substrate giving 2-arylated product in 32% yield, whereas under the same reaction conditions the sulfur analogue provides 54% of 2-substituted-thiophene 9c (Scheme 10.37). Pyrroles are the most reactive heterocycles, and 2-arylated products 9a-b are found with 64% and 75% yields using pyrrole and 2,4-dimethyl-pyrrole, respectively. Only with 2,5-dimethylated furan and pyrrole, will arylation... 

The photoisomerization of 2-substituted thiophenes into the corresponding 3-substituted derivatives is a common pathway observed for both 2-aryl and 2-alkylthiophenes [4]. However, for synthetic applications, a significant example can be recognized in the photoisomerization of 2-arylthiophenes 33 into the corresponding 3-aryl derivatives 34 by the large-scale irradiation in Et20 with a high-pressure Hg lamp (Scheme 12.10) [28]. 

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