Thallation electrophilic aromatic

Mercuration of aromatic compounds can be accomplished with mercuric salts, most often Hg(OAc)2 ° to give ArHgOAc. This is ordinary electrophilic aromatic substitution and takes place by the arenium ion mechanism (p. 675). ° Aromatic compounds can also be converted to arylthallium bis(trifluoroacetates), ArTl(OOCCF3)2, by treatment with thallium(III) trifluoroacetate in trifluoroace-tic acid. ° These arylthallium compounds can be converted to phenols, aryl iodides or fluorides (12-28), aryl cyanides (12-31), aryl nitro compounds, or aryl esters (12-30). The mechanism of thallation appears to be complex, with electrophilic and electron-transfer mechanisms both taking place. 

A simple, high-yield procedure for the conversion of ArTlXj into ArjTlX compounds has recently been described 90). This symmetrization reaction, the mechanism of which is not known, can be effected by treatment of the ArTlX2 compound either with triethyl phosphite or with hot aqueous acetone. As a wide variety of ArTlXj compounds can now be easily prepared by electrophilic thallation of aromatic substrates with thallium(III) trifluoroacetate (q. v.), symmetrization represents the method of choice for the preparation of the majority of ArjTlX compounds. Only about twenty mixed compounds, RR TIX, have been prepared so far, and the only general synthetic procedure available consists of a disproportionation reaction between an RTIX2 species and another organometallic reagent [e.g., Eqs. (5)-(7)]. 

TFA. Electrophilic aromatic thallation with TTFA therefore constitutes a simple and general procedure for the preparation of monoarylthallium(III) derivatives and has been the subject of detailed kinetic, mechanistic, and synthetic investigations. These aspects of the thallation reaction are discussed at length below. 

The reactions of aromatic substrates with thallium reagents is a fascinating subject which has been reviewed by McKillop and Taylor,two of the prime contributors to this field of chemistry. Two types of reaction are possible, both of which are important for the introduction of oxygen functionality. Tlie fu t is electrophilic aromatic thallation, whilst the second involves one-electron oxidation. 

Arylthallium(in) compounds (83) are generally prepared by electrophilic aromatic thallation with thallium tris(trifiuoroacetate) (84). 

The major advantage of thallation is orientational specificity. While thallation is essentially all para to alkyl groups, halides and alkoxy substituents, orientation is almost all ortho to a carboxyl or an ester substituent. We see that such orientation to ester and carboxyl substituents is unusual in that these groups are typically meta-directing in electrophilic aromatic substitution. This behavior can be attributed to an intramolecular interaction involving the electrophilic thallium and the carbonyl group which allows for facile ortho substitution. 

Thallium fill). - The electrophilic thallation of aromatic groups has led to new organothallium(III) species. 

Thallation of thiophens in the 2-position with thallium(m) trifluoro-acetate in trifluoroacetic acid is complete within a few minutes at room temperature. The thallium derivative reacts in situ with aqueous potassium iodide solution to give a convenient and high-yield synthesis of iodo-thiophens. A mixture of thallium(m) acetate has been shown to be a mild and efficient reagent for electrophilic aromatic bromination. Thiophen yields 2-bromothiophen in 82% yield and very little dibromothiophen. 3-Methylthiophen appears to be selectively brominated in the 2-position and 2-methylthiophen in the 5-position in 70—75% yield. The direct thiocyanation of thiophen and some alkylthiophens with thiocyanogen under various conditions using a variety of Friedel-Crafts catalysts has... 

Electrophilic mercuration and thallation of aromatic compounds, alkenes and alkynes are considered in Chapter 3. 

Complex 13 undergoes electrophilic substitution with aromatic substrates. Thus, treatment with benzene in dichloromethane at ambient temperature results in the formation of the diphenyl complex 15 (Scheme V. Reaction of 13 with pyridine (5-6 equivs) in dichloromethane affords a new complex that is the result of pyridine a-CH activation. The NMR data clearly show two chemically equivalent coordinated pyridines and pyridine that has lost one of the a-hydrogens. Structure 16 is proposed from the preliminary data. The formation of 15 and 16 was quantitative by NMR monitoring, but these compounds are reactive and have not been isolated as pure solids. While main group Lewis acids are well known to undergo aromatic substitutions (e.g., mercurations, thallations, etc.) (33), relatively little is known about the ability of transition metal complexes to undergo electrophilic aromatic substitution (34). 

With the ArH ArTlX2 Arl reaction sequence available as a rapid and reliable probe for aromatic thallation, a detailed study was undertaken of the various factors affecting orientation in this electrophilic metallation process (153). The results, which are summarized below, demonstrate that aromatic thallation is subject to an almost unprecedented degree of orientation control coupled with the ease with which thallium can then be displaced by other substitutent groups (this aspect of the synthetic exploitation of aromatic thallation is discussed in detail below), the sequential processes of thallation followed by displacement represent a new and versatile method for aromatic substitution which both rivals and complements the classic Sandmeyer reaction. 

Aromatic thallation has been shown to be a reversible electrophilic substitution reaction with an energy of activation of approximately 27 kcal/mole and an extremely large steric requirement 153). The consequence of the latter feature of aromatic thallation is that there is a significant preference for para substitution in thallation of simple monosubstituted benzeno id compounds. It will be seen by examination of Table VI that the amount of para substitution increases as the size of the substituent increases (for... 

The aryl-thallium bond is thus apparently capable of displacement either by electrophilic or by suitable nucleophilic reagents. Coupled with its propensity for homolytic cleavage (spontaneous in the case of ArTlIj compounds, and otherwise photochemically induced), ArTlXj compounds should be capable of reacting with a wide variety of reagents under a wide variety of conditions. Since the position of initial aromatic thallation can be controlled to a remarkable degree, the above reactions may be only representative of a remarkably versatile route to aromatic substitution reactions in which organothallium compounds play a unique and indispensable role. 

The electrophilic thallation path involves [T1(TFA)2]+ as the active electrophile which forms a jt-complex with the substrate [16, 31]. Single electron transfer from electron-enriched polymethylarenes can be significant, leading to the formation of biaryls and side-chain thallated products [31]. The electron transfer path during electrophilic metalation is much more characteristic of T1(TFA)3 than Hg(TFA)2 [16], A review article [29] includes useful analysis of mechanistic features of aromatic thallation with T1(TFA)3 and some other Tl(III) reagents, including the even more electrophilic triflate. 

Although thallium(III) acetate fails to react with aromatic compounds under mild conditions, thallium (III) trifluoroacetate will effect rapid electrophilic thallation of a wide range of aromatic substances (40, 168, 169, 170, 203) according to the general reaction [Eq. (11)]. These reactions are very rapid and are usually completed in a few minutes at room temperature for activated aromatic nuclei, to give stable colorless solids that generally crystallize from solution. The orientation of thallation in such reactions may be influenced by temperature [Eq. (13)], or by the substituents on the aromatic nucleus. 

Thallium compounds are very poisonous, and must be handled with extreme care. Although substituent groups affect the reactivity of the aromatic substrate as expected for electrophilic substitution, orientation is unusual in a number of ways, and it is here that much of the usefulness of thallation lies. Thallation is almost exclusively para to —R, -Cl, and OCH3, and this is attributed to the bulk of the electrophile, thallium trifluoroacetate, which seeks out the uncrowded para position. 

Aromatic iodides (3,287). The definitive paper on the synthesis of aromatic iodides by the reaction of arylthallium ditrifluoroacetates with potassium iodide has been published.1 Four procedures have been developed. 1) Thallation is carried out as usual and then an aqueous solution of potassium iodide is added directly. 2) The intermediate arylthallium ditrifluoroacetate is isolated and then treated with potassium iodide. 3) For acid-sensitive substrates solid TTFA in acetonitrile is used for thallation. 4) These methods are unsuccessful with highly reactive compounds such as naphthalene and diphenyl. In such cases molecular iodine is used as the electrophilic reagent and TTFA is used as oxidant for the hydrogen iodide formed in the reaction. 

Thallium(III) isobutyrate, a weak electrophile, limits the range of aromatic substrates that can be thallated. Even for activated substrates, 100-110 C is required. 

One important mechanism for homogeneous catalytic activation of aromatic C—H bonds is electrophilic attack by transition-metal complexes on the aromatic substrates. It is presumed t -aryl complexes are important intermediates in these reactions, but they are rarely isolated. Direct electrophilic metallation of aromatic substrates is closely related to reactions observed with nontransition metals ( 5.6., auration 5.7.2., mercuration and 5.3., thallation - ). References to metal-aryl complexes synthesized by electrophilic attack on arenes by transition metals are sununarized in Table 1. Reviews are available " . 

Synthesis of indoles via 2,3-dihydroindoles (indolines) is sometimes done in order to achieve a specific substitution pattern in the carbocyclic ring <67RCR753>. Indolines, being aniline derivatives, readily undergo electrophilic substitution at C5. Indolines can also be used to achieve selective 7-substitution. The 1-Boc derivative of indoline can be lithiated at C7 <92H(34)i03i> and 1-acetyl-indoline is thallated at C7 <89H(29)643>. These organometallic intermediates can be functionalized and then aromatized to indoles. There are a number of methods which have been developed for oxidative aromatization of dihydroindoles. Table 3 cites some examples. 

Consider thallation, an electrophilic substitution of an aromatic compound by a trivalent thallium compound, depicted below for benzene and T1(02CCF3)3 ... 

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