Thiophene radical attack

It is estimated that thiophene reacts with phenyl radicals approximately three times as fast as benzene. Intramolecular radical attack on furan and thiophene rings occurs when oxime derivatives of type (112) are treated with persulfate (8UCS(Pt)984). It has been found that intramolecular homolytic alkylation occurs with equal facility at the 2- and 3-positions of the thiophene nucleus whereas intermolecular homolytic substitution occurs mainly at position 2. 

The mechanism of the reaction of thiophene with a variety of radicals as a function of pH has been studied using ESR (81JCS(P2)207). Attack by -OH at pH 6 proceeds by direct addition with a preference to add to the a-position the ratio of (226) to (227) is 4 1. At low pH the (3-adduct easily loses OH- to form the thiophene radical-cation, which may undergo rehydration. In the case of 2-methyIthiophene the radical-cation deprotonates to give the thenyl radical this is reminiscent of the electrochemical oxidation (Section 3.14.2.6). The radical-cations are also formed by direct electron abstraction from the thiophene substrates by chlorine anion-radicals. At pH >6, (226) starts disappearing with formation of ring-opened products (Scheme 61). 

The most vexed subject in this field is the site of radical attack on substituted aromatic rings. Some react cleanly where we should expect them to. Phenyl radicals add to naphthalene 7.36, to anthracene 7.37 and to thiophene 7.38, with the regioselectivity shown on the diagrams. In all three cases, the frontier orbitals are clearly in favour of this order of reactivity (because of the symmetry in these systems, both HOMO and LUMO have the same absolute values for the coefficients). 

Figure 62 Polythiophene formation via mechanism involving radical attack upon neutral thiophene monomer. (From Ref. 263.)...

The most vexed subject in this field is the site of radical attack on substituted aromatic rings. Some react cleanly where we should expect them to. Phenyl radicals add to naphthalene (399), to anthracene (400)323 and to thiophene... 

Unlike thiophene radical cation the SOMO for this species is 2bl with considerable spin density on sulfur. The reversible electrochemical oxidation potentials for 129 and some of its derivatives in l,l,l,3,3,3-hexafluoro-2-propanol are listed in Table 8. The reactions of 129 with radicals and with nucleophiles has been studied [275]. The position of attack by radicals on 129 should reflect the spin density at that position as found by EPR spectroscopic analysis. Indeed reaction with N02 occurs predominantly at S, C(2) and C(4) as expected. The valence bond configuration mixing model leads to the prediction that nucleophiles should preferentially attack 129 at C(l) and C(3) with little attack at S, C(2) and C(4). This is partly but not completely validated experimentally. Radi-... 

In homolytic aromatic substitution, a radical attacks an aromatic ring leading to the formation of a o-complex, which, after the loss of a leaving group, usually hydrogen (H), is converted into the substitution product. In many cases, the oxidation step is also involved in the process the radical o-complex is oxidised to give a cationic o-complex, which, in turn, loses a proton thus forming the final product [199]. The formation of radical o-complexes (Scheme 134) upon attack of a radical on thiophene was confirmed by ESR spectroscopy [200]. 

Another approach to functionalisation of thiophene itself, where thiophene is attacked by another aryl radical, was performed using only f-BuOK in DMSO as the reagent [206]. Under photostimulation, aryl halides were converted into aryl anion radicals [Ar-X], and these disproportionated to halide anion (X ) and aryl radical (Ar ). The reaction of thiophene (Th-H) with radical Ar gave the new radical (Ar-Th-H ). Here f-BuOK was called upon to deprotonate the radical and to produce a new anion radical (Ar-Th ), which by SET to starting halide is converted into a neutral compound - final product Ar-Th. Using this sequence, several products in good or excellent yields were obtained albeit with low regioselectivity (examples in Scheme 143) [206]. 

These results show that in the phenylation of thiazole with benzoyl peroxide two secondary reactions enter in competition the attack of thiazole by benzoyloxy radicals, leading to a mixture of thiazolyl benzoates, and the formation of dithiazolyle through attack of thiazole by the thiazolyl radicals resulting from hydrogen abstraction on the substrate and from the dimerization of these radicals. This last reaction is less important than in the case of thiophene but more important than in the case of pyridine (398). 

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, ... 

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 electrochemical oxidation of 2,5-dimethylthiophene in various electrolytes has been investigated (71JOC3673). In non-halide electrolytes such as ammonium nitrate or sodium acetate, the primary anodic process is the oxidation of the thiophene to the cation-radical (159). Loss of a proton, followed by another oxidation and reaction with solvent methanol, leads to the product (160) (Scheme 31). When the electrolyte is methanolic NaCN, however, nuclear cyanation is observed in addition to side-chain methoxylation. Attack by cyanide ion on the cation-radical (159) can take place at either the 2- or the 3-position, leading to the products (161)-(163) (Scheme 32). 

In homolytic substitution reactions, the 2-position of thiophene is the preferred site of attack. This is easily rationalized in terms of frontier orbital theory (B-76MI31401). Because of symmetry, both HOMO and LUMO of thiophene have the same absolute values for the coefficients (as shown in 216). Thus it is immaterial whether the [SOMO (radical)-HOMO (thiophene)] or the [SOMO (radical)-LUMO (thiophene)] interaction determines the site of attack only the 2-position is the point at which the radical would attack. The same conclusion is iso reached by consideration of product development control (74AHC(16)123). Attack at the 2-position would result in a transition state with an allylic radical, which would be stabilized to a greater extent than the one arising from attack at position 3 (Scheme 57). 

Attack at the 2-position has been effected with stabilized radicals such as benzyl and triphenylmethyl. Substitution has also been observed with alkylthio, phenylethynyl and thienyl radicals since the latter two are very reactive, substitution occurs at both positions 2 and 3 (73US295). Thiophene can also be homolytically aminated with amino cation-radicals, leading to 2-dialkylamino derivatives (74AHC(16)123>. 

Two situations are conducive to ipso attack. If polar effects come into play in stabilizing the transition state of the addition of the radical, then frequently ipso attack is encountered. This is clearly brought out in the different behaviour of adamantyl and methyl radicals towards the same substrate. It has been firmly established that while methyl and phenyl radicals are electroneutral, the bridgehead adamantyl radical behaves as a nucleophilic species (80ACR51). If this adamantyl radical is reacted with thiophene substrates made electron deficient by the presence of suitable substituents, then the transition state of the addition step may have the character of a charge-transfer complex the site at which the... 

The homolytic arylation of benzo[6]furan has been studied using aryl radicals generated by decomposition of 1,3-diaryltriazenes in the presence of isopentyl nitrite at 120 °C (79JHC97), or phenyl radicals produced by the decomposition of N- nitrosoacetanilide at 40 °C. The major position of attack is the 2-position (75.9%), but some occurs at the 4-(17.5%) and 7-positions (6.6%). Benzo[6]furan is 8.3 times more reactive than benzene and 1.26 times more reactive than benzo[6 ]thiophene. 

This approach to the thiophene ring seems most direct and involves (1) intramolecular nucleophilic addition of thiol, thiolate, and dithiocarboxylate sulfurs and, in a rare case, sulfide sulfur to sp and sp carbons (2) electrophilic attack of sulfenium and sulfonium ions and their equivalents on unsaturated carbon-carbon bonds (3) addition of thiyl radicals to unsaturated carbon-carbon bonds (4) addition of vinyl and aryl radicals to the sulfur atom of sulfides and (5) electrophilic attack of a carbocation on the sulfur atom of sulfides. 

Another mechanistic possibility is the attack of the thiophene cation radical (420) upon a neutral thiophene monomer (419) to form a cation-radical dimer (421) [247]. The oxidation and loss of two protons leads to formation of the neutral dimer (422). Once again, rapid oxidation of the dimer occurs upon its formation due to its close proximity to the electrode surface and its lower oxidation potential. The cation-radical dimer (423) which is formed then reacts with another monomer molecule in a similar series of steps to produce the trimer 425. A kinetic study of the electrochemical polymerization of thiophene and 3-alkylthiophenes led to the proposal of this mechanism (Fig. 61) [247]. The rate-determining step in this series of reactions is the oxidation of the thiophene monomer. The reaction is first order in monomer concentration. The addition of small amounts of 2,2 -bithiophene or 2,2 5, 2"-terthiophene to the reaction resulted in a significant increase in the rate of polymerization and in a lowering of the applied potential necessary for the polymerization reaction. In this case the reaction was 0.5 order in the concentration of the additive. 

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