Substituted Thiophens

Substituted Thiophens. Aryl-substituted thiophens cannot be planar, and several theoretical studies have been made to predict preferred conformations. EHT computations for 2- and 3-phenylthiophen (40) predict an angle of distortion of 37° between the two planes of the cyclic ir-systems the electron distribution in these conformations was calculated by the CNDO/2-approach and comparison was made between the theoretical and experimental dipole moments. The calculations were later extended to (41) and its hetero-analogues. Bond-length calculations predict a very long bond between the heterocycles, which largely preserves the geometries of individual furan and thiophen ring systems. 

The planar conformations of (42) have excited strong interest ir-type ° as well as all-valence-electron SCF calculations ° show the S, 0-cis conformer to be more favoured than the S, 0-trans form, a finding 

Schwartz and J. D. Switalski, Proceedings of the International Conference on Electron Spectroscopy, 1971, ed. D. A. Shirley, North Holland, Amsterdam, 1972, J. Amer. Chem. Soc., 1974, 94, 6298. 

A PPP study of (43) has shown that the unsaturated side chain should be energetically preferred in the s-trans arrangement.  

Theoretical methods have been applied to elucidate tautomeric equilibria. In agreement with the experimental finding, the A -thiolen-2-one (44a) was calculated to be more stable than the hydroxythiophen (44). Tautomeriza-tion of thiophen analogues of anthrone, e.g. (45), was discussed in the light of the differences in HMO energies.  

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Dyestuffs. The use of thiophene-based dyestuffs has been largely the result of the access of 2-amino-3-substituted thiophenes via new cycHzation chemistry techniques (61). Intermediates of type (8) are available from development of this work. Such intermediates act as the azo-component and, when coupled with pyrazolones, aminopyrazoles, phenols, 2,6-dihydropyridines, etc, have produced numerous monoazo disperse dyes. These dyes impart yeUow—green, red—green, or violet—green colorations to synthetic fibers, with exceUent fastness to light as weU as to wet- and dry-heat treatments (62-64). 

The synthesis involves the nickel-catalyzed coupling of the mono-Grignard reagent derived from 3-alkyl-2,5-diiodothiophene (82,83). Also in that year, transition-metal hahdes, ie, FeCl, MoCl, and RuCl, were used for the chemical oxidative polymerization of 3-substituted thiophenes (84). Substantial decreases in conductivity were noted when branched side chains were present in the polymer stmcture (85). 

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). ... 

The stable Dewar thiophene (68) is obtained by irradiation of 2,3,4,5-tetrakis(trifluoromethyl)thiophene (Scheme 150) (72ClC272l). Dewar thiophenes are proposed as intermediates in the photochemical isomerizations of substituted thiophenes (Scheme 17). 

The Hinsberg thiophene synthesis has seen limited use owing to the potential for regioisomeric mixtures when unsymmetrical 1,2-dicarbonyls are condensed with unsymmetrical thiodiacetates. Thus, symmetrically substituted thiophenes are generally prepared in this manner. 

Quantum-mechanical calculations on substituted thiophenes are still more difficult and localization energies and electronic charges have been calculated only for 2- and 3-nitrothiophene. ... 

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-... 

The study of the NMR spectra of thiophenes has attracted considerable interest, 22,24-3sb partly because the spectra of substituted thiophenes containing only a few ring hydrogens are quite suitable for complete analysis and partly because in a series of related compounds the chemical shifts observed are related to differences in the electron distribution about chemically nonequivalent hydrogens (for review, see reference 39), especially for hydrogens far removed from the substituent. 

Chemical Shifts (ppm) of Substituted Thiophenes, Relative TO the Shifts of the a- and /3-Hydrogens in Thiophene... 

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

The larger shifts of hydrogen 2 in 3-substituted thiophenes than those of hydrogen 3 in 2-substituted, have been ascribed to the greater probability of structures (12) and (18) over (2) and (7). 

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 chemical shifts of the methyl groups of 5-substituted 2-methyl-thiophenes have been found to be approximately proportional to the shifts of the 2-ring hydrogen in 5-substituted thiophenes and thus dependent both on the mesomeric and on the inductive effects of the substituents. ... 

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... 

Many 3-substituted thiophenes have a characteristic absorption at 760-780 Typical absorption bands exist for the different... 

Although the UV spectra of a large number of substituted thiophenes have been recorded by many authors during recent years, the first systematic studies of the UV spectra of monosubstituted thiophenes designed to obtain information about differences in the influence of substituents in 2- and 3-substituted thiophenes were carried out independently by Andrisano and Pappalardo and by the present author. ... 

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... 

The —I—M 3-substituted thiophenes in alcohol show only one band, and, as is found in the 2-isomer, this is displaced (with increased extinction) toward longer wavelength with increasing conjugating power of the substituent. It is probable that this is the displaced 235-m/A band of thiophene, since the spectra of 3-acetylthio-phene and 3-cyanothiophene also show a primary band at about 225 mju, in hexane solution. ... 

The smaller bathochromatic shift of the thiophene chromophore in 3-substituted thiophenes compared with that of the 2-isomers gives additional evidence that the 2-position in thiophenes affords more effective conjugation than the 3-position. ... 

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-... 

The reduction of the C— Br and C—1 group moments from 1.10 and 0.90 in bromo- and iodo-benzene to about 0.80 and 0.50 in 2-bromo- and 2-iodo-thiophene has been ascribed to the larger weight of resonance forms such as (8) and (9) in the thiophene series. The chlorine, nuclear, quadrupole, resonance frequencies of chloro-substituted thiophenes are much higher than those of the corresponding benzene derivatives. This has been ascribed to a relayed inductive effect originating in the polarity of the C—S o-bond in thiophenes. The refractive indices, densities, and surface tension of thiophene, alkyl- and halo-thiophenes, and of some other derivatives have been... 

Substituted thiophenes, such as 2-iodo-, 2-bromo-, 2 chloromethyl-, and 2-acetyl-thiophene have been obtained by reacting crude, coal-tar benzene with the appropriate reagents. ... 

Dichlorothiophene has become easily available through chlorination and dehydrochlorination of tetrahydrothiophened Another example of the aromatization of tetrahydrothiophene derivatives is the preparation of 3-substituted thiophenes by the reaction of 3-ketotetrahydrothiophene with Grignard reagents followed by the aromatization of the intermediate dihydrothiophene. Recent gas chromatographic analysis showed, however, that 2,3-dichlorothio-phene is the main product from the dehydrochlorination of tetra-chlorotetrahydrothiophene. 

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. 

Until recently, 3-substituted thiophenes have been rare and difficultly available compounds, as they, with very few exceptions, cannot be prepared by direct substitution of thiophene. 

Campaigne et al. have used 3-thenyl bromide obtained by benzoyl peroxide-catalyzed, side-chain bromination of 3-methylthiophene with A -bromosuccinimide, as a starting material for 3-substituted thiophenes. - 22 3-Methylthiophene is now prepared commercially from itaconic acid. The reactive halogen in 3-thenyl bromide could be directly reacted with a variety of nucleophiles, such as cyanide, or malonate, to give more complex 3-substituted compounds. 3-Thenyl bromide was converted by the Sommelet reaction to 3-thio-phenealdehyde which, with silver oxide, was oxidized to 3-thio-... 

Grignard reagents has been introduced by Wynberg et for the preparation of 3-substituted thiophenes. 

By reaction of 3-thienyllithium with magnesium bromide, the Grignard reagent, free from entrainment Grignard reagent, was obtained,- which is useful for the preparation of 3-acetothiophene by reaction with acetic anhydride at —70 0 and for the preparation of 3-t-butoxythiophene through reaction with t-butyl perbenzoate. It is the opinion of the present author that most 3-substituted thiophenes are prepared more conveniently from 3-thienyllithium than from 3-thenyl bromide. The latter method, however, is superior if the introduction of the 3-thenyl group is desired. 

Dichlorothiophene can also be used for the synthesis of 3-substituted thiophenes, since it can be smoothly acylated and chloro-methylated in the 3-position, and the halogens can then be readily removed at the appropriate stage. 3-Thenylsuccinic acid (28) has thus been obtained by treating 2,6-dichloro-3-thenylsuccinic acid with sodium amalgam. 2-Bromo-3-thenylbromide can be utilized in a similar way. ... 

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-... 

A comparison of the polarographic reduction of 2- and 3-substituted thiophenes have shown that the 2-isomers are more easily reduced than the 3-isomers. Polarography has also been used for the quantitative study of the dehalogenative reduction of 2-halo-5-carbonyl thiophenes and for the study of the hydroxychalcone-chromanone equilibrium in thienylsubstituted compounds. ... 

Melles and Backer " found, from a study of the oxidation of substituted thiophenes with perbenzoic or peracetic acid, that sulfones could be obtained from polysubstituted methyl- and phenyl-thiophenes and that the presence of electron-attracting groups, such as nitro, hindered the oxidation. Oxidation of thiophene - led to a product which was formed through a Diels-Alder reaction between the intermediate thiophene sulfoxide (211) and thiophene sulfone (212) and for which two alternative structures, (213) or (214), were suggested. Similar sesquioxides were also obtained from 2- and 3-methylthiophene and 3-phenylthiophene. The structures were not proved. Bailey and Cummins synthesized thiophene-1,1-dioxide... 

In the desulfurization of 3-substituted thiophenes several stereoisomers may be formed in certain cases. Both meso and racemic compounds have been obtained from the desulfurization of 3,4-diaryl-substituted thiophenes. It is claimed, however, that only meso, -diphenyladipic acid is obtained upon desulfurization of 3,4-di-phenyl-2,5-thiophenedicarboxylic acid and only di-isoleucin from 3-thienylglycine. The formation of small amounts of dimeric products in the desulfurization has been discussed with reference to the mechanism of this reaction. ... 

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). 

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