Aromatic substitution thallation

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. 

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. 

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 linear free enogy relationship obsoved for arene donors relates the activation barrier AG for aromatic substitution directly to the CT transiticxi oiergy Aver of the EDA complex. Since Aver pertains to the energetics of the photoionizadons in equations (27) and (28), the correlation suggests that these arene contact ion pairs ate reasonable approximatims to the transition states for both mercuration and thallation, e.g. Scheme 6. 

This sequential process of thallation followed by displacement represents a new and versatile method for aromatic substitution. 

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. 

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). 

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... 

From the point of view of the synthetic organic chemist, the importance of aromatic thallation, and the remarkable degree of orientation control which can be exercised over this process, lies in the ease with which the resulting ArTlXj compounds can be converted into substituted aromatic derivatives in which the new substituent group has entered the ring at the position to which thallium was originally attached. Syntheses of phenols, nitroso compounds, biaryls, aromatic nitriles, thiophenols, and deuterated aromatic compounds have all been achieved these results are summarized briefly below. 

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. 

Under conditions of kinetic control (low T and short times), the orientation of aromatic thallation relative to substituents on the ring may generally be predicted by normal meta- vs. ortho-para-directing character of the substituents . For ortho-para directors, para substitution predominates owing to the steric requirements of the Tl reagent. 

Thallium carboxylates, particularly the acetate and trifluoroacetate, which can be obtained by dissolution of the oxide in the acid, are extensively used in organic chemistry.14 Both Tl metal and Tl1 salts such as the acetylaceton-ate also have specific uses. One example is the use of thallium(m) acetate in controlled bromination of organic substances such as anisole. The trifluoroacetate will directly thallate (cf. aromatic mercuration, Section 18-9) aromatic compounds to give aryl thallium ditrifluoroacetates, e.g., C6H5Tl(OOCCF3)2. It also acts as an oxidant, inter alia converting para-substituted phenols into p-quinones. 

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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