Electrophilic aromatic substitution position selectivity

Other matters that are important include the ability of the electrophile to select among the alternative positions on a substituted aromatic ring. The relative reactivity of different substituted benzenes toward various electrophiles has also been important in developing a firm understanding of electrophilic aromatic substitution. The next section considers some of the structure-reactivity relationships that have proven to be informative. 

The table below gives first-order rate constants for reaction of substituted benzenes with w-nitrobenzenesulfonyl peroxide. From these data, calculate the overall relative reactivity and partial rate factors. Does this reaction fit the pattern of an electrophilic aromatic substitution If so, does the active electrophile exhibit low, moderate, or high substrate and position selectivity ... 

Ipso substitution, in which the electrophile attacks a position already carrying a substituent, is relatively rare in electrophilic aromatic substitution and was not explicitly covered in Section 10.2 in the discussion of substituent effects on reactivity and selectivity Using qualitative MO cOTicepts, discuss the effect of the following types of substituents on the energy of the transition state for ipso substitution. 

Electrophilic aromatic substitution of nitrobenzene occurs selectively at the meta position. 

The reason for this difference in selectivity of different electrophilic reagents between the 2- and 3-positions must be sought in the finer details of the mechanism of electrophilic aromatic substitution Melander and co-workers are studying this problem by means of isotope effects. 

The a-selectivity is illustrated by the fact that 2-alkyl-, > 2-methoxy-, > and 2-alkyIthio-thiophenes and alkyl thenyl sul-fides ° are metalated exclusively in the 5-position. In electrophilic aromatic substitution, as previously mentioned, an appreciable amount of 3-substitution is obtained with some of these groups. After acetalization ketones can also be metalated. Thus from the diethyl ketal of 2-acetylthiophene, 2-acetyl-5-thiophenealdehyde was obtained after metalation with n-butyllithium followed by the reaction of the metalorganic compound with A,A -dimethylformamide. ... 

These polarizations are seen to be in the opposite direction to those in aniline (3.133), so that higher pi density remains at the Ci (junction) and C3 and C5 (meta) positions. These polarity shifts are again consistent with the well-known m-directing effect of nitro substituents in electrophilic aromatic substitution reactions, and the results are again quite independent of which starting Kekule structure is selected for the localized analysis.63... 

Hence the positional selectivity is different from that of the furan additions to 417 (Scheme 6.90). Assuming diradical intermediates for these reactions [9], the different types of products are not caused by the nature of the allene double bonds of 417 and 450 but by the properties of the allyl radical subunits in the six-membered rings of the intermediates. Also N-tert-butoxycarbonylpyrrole intercepted 450 in a [4 + 2]-cycloaddition and brought about 455 in 29% yield. Pyrrole itself and N-methylpyr-role furnished their substituted derivatives of type 456 in 69 and 79% yield [155, 171b]. Possibly, these processes are electrophilic aromatic substitutions with 450 acting as electrophile, as has been suggested for the conversion of 417 into 442 by pyrrole (Scheme 6.90). 

The selective electrophilic aromatic substitution carried out by displacement of a metallic substituent (Hg, Sn) ( F-fluorodemetallation) using [ F]p2 or [ F]AcOF remains a method of choice to introduce a fluorine atom on a specific position. In the early preparations of [6- F]fluoro-L-DOPA, the reaction of a 6-substituted mercuric derivative with [ F]acetyl hypofluorite yielded the expected compound in 11 % yield [73,74]. Reaction of a mercuric precursor, free or on a modified polystyrene support P-CH2-COOHg(DOPA precursor) allows the preparation of [ F]fluoro-L-DOPA in an overall yield up to 23 %. The polymer supports are easily prepared, require no special treatment for storage and are convenient to use in automated production [75]. 

Such a representation is referred to as a local ionization potential map. Local ionization potential maps provide an alternative to electrostatic potential maps for revealing sites which may be particularly susceptible to electrophilic attack. For example, local ionization potential maps show both the positional selectivity in electrophilic aromatic substitution (NH2 directs ortho para, and NO2 directs meta), and the fact that TC-donor groups (NH2) activate benzene while electron-withdrawing groups (NO2) deactivate benzene. 

Molten 2-ethoxybenzoic acid (7) was added to a mixture of chlorosulfonic acid and thionyl chloride while keeping the reaction temperature below 25 °C. In this straightforward electrophilic aromatic substitution the ethoxy group directs the electrophile towards the ortho and para position whereas the carboxylic acid directs meta giving an overall selectivity for the attack at C-5. It was necessary to add thionyl chloride to transform the intermediate sulfonic acid into... 

Comparison of results from the gas-phase proton-induced unimolecular isomerization of (R)- -d -3-(p-fluorophcnyl )bulanc (11) with the positional selectivity of the corresponding gas-phase bimolecular arene alkylation confirms the presence of non-covalent j-type intermediates and their important role in determining the intramolecular selectivity of gas-phase electrophilic aromatic substitutions.20... 

A more suitable explanation can be suggested for this case, which makes use of the present model. Because at the transition state the substrate acquires a partial radical-anionic character, the radical anion of the substrate should be examined. The positional selectivity will most likely be determined by the location of the unpaired spin population in the model radical anion, toward which the radicaloid nucleophile will be attached in order to complete bond formation. A similar argument was invoked by Kochi (27) to explain the positional selectivities observed in electrophilic aromatic substitution. 

The general mechanistic framework outlined in this section can be elaborated by other details to more fully describe the mechanisms of the individual electrophilic substitutions. The question of the identity of the active electrophile in each reaction is important. We have discussed the case of nitration in which, under many circumstances, the electrophile is the nitronium ion. Similar questions about the structure of the active electrophile arise in most of the other substitution processes. Another issue that is important is the ability of the electrophile to select among the alternative positions on a substituted aromatic ring position selectivity). The relative reactivity and selectivity of substituted benzenes toward various electrophiles is important in developing a firm understanding of EAS. The next section considers some of the structure-reactivity relationships that have proven to be informative. 

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