Electrophilic species

Nitration can be effected under a wide variety of conditions, as already indicated. The characteristics and kinetics exhibited by the reactions depend on the reagents used, but, as the mechanisms have been elucidated, the surprising fact has emerged that the nitronium ion is preeminently effective as the electrophilic species. The evidence for the operation of other electrophiles will be discussed, but it can be said that the supremacy of one electrophile is uncharacteristic of electrophilic substitutions, and bestows on nitration great utility as a model reaction. 

In more dilute solutions the concentration of the nitronium ion falls below the level of spectroscopic detection, and the nature of the electrophilic species has been the subject of conjecture. 

The selectivity of an electrophile, measured by the extent to which it discriminated either between benzene and toluene, or between the meta- and ara-positions in toluene, was considered to be related to its reactivity. Thus, powerful electrophiles, of which the species operating in Friedel-Crafts alkylation reactions were considered to be examples, would be less able to distinguish between compounds and positions than a weakly electrophilic reagent. The ultimate electrophilic species would be entirely insensitive to the differences between compounds and positions, and would bring about reaction in the statistical ratio of the various sites for substitution available to it. The idea has gained wide acceptance that the electrophiles operative in reactions which have low selectivity factors Sf) or reaction constants (p+), are intrinsically more reactive than the effective electrophiles in reactions which have higher values of these parameters. However, there are several aspects of this supposed relationship which merit discussion. 

Among the variety of electrophilic species present m concentrated sulfuric acid sulfur tnoxide (Figure 12 4) is probably the actual electrophile m aromatic sulfonation We can represent the mechanism of sulfonation of benzene by sulfur tnoxide by the sequence of steps shown m Figure 12 5... 

Secondary alkyl halides react by a similar mechanism involving attack on benzene by a secondary carbocation Methyl and ethyl halides do not form carbocations when treated with aluminum chloride but do alkylate benzene under Friedel-Crafts conditions The aluminum chloride complexes of methyl and ethyl halides contain highly polarized carbon-halogen bonds and these complexes are the electrophilic species that react with benzene... 

Electrophilic aromatic substitution (Section 12 1) Fundamen tal reaction type exhibited by aromatic compounds An electrophilic species (E" ) attacks an aromatic ring and re places one of the hydrogens... 

In the presence of strongly acidic media, such as triflic acid, hydrogen cyanide or trimethylsilyl cyanide formylates aromatics such as ben2ene. Diprotonotated nittiles were proposed as the active electrophilic species in these reactions (119). 

Friedel-Crafts acylation using nittiles (other than HCN) and HCI is an extension of the Gattermann reaction, and is called the Houben-Hoesch reaction (120—122). These reactions give ketones and are usually appHcable to only activated aromatics, such as phenols and phenoHc ethers. The protonated nittile, ie, the nitrilium ion, acts as the electrophilic species in these reactions. Nonactivated ben2ene can also be acylated with the nittiles under superacidic conditions 95% trifluoromethanesulfonic acid containing 5% SbF (Hg > —18) (119). A dicationic diprotonated nittile intermediate was suggested for these reactions, based on the fact that the reactions do not proceed under less acidic conditions. The significance of dicationic superelectrophiles in Friedel-Crafts reactions has been discussed (123,124). 

In this section three main aspects will be considered. Firstly, the basic strengths of the principal heterocyclic systems under review and the effects of structural modification on this parameter will be discussed. For reference some pK values are collected in Table 3. Secondly, the position of protonation in these carbon-protonating systems will be considered. Thirdly, the reactivity aspects of protonation are mentioned. Protonation yields in most cases highly reactive electrophilic species. Under conditions in which both protonated and non-protonated base co-exist, polymerization frequently occurs. Further ipso protonation of substituted derivatives may induce rearrangement, and also the protonated heterocycles are found to be subject to ring-opening attack by nucleophilic reagents. 

Indole undergoes add-catalyzed dimerization the 3H-indoIium ion acts as an electrophile and attacks an unprotonated molecule to give the dimer (46). Protonation of the dimer in turn gives an electrophilic species from which a trimeric product can be derived (77CPB3122). Af-Methylisoindole undergoes acid-catalyzed polymerization, indicating that protonation at C-1 gives a reactive electrophilic intermediate. 

The chemical reactivity of these two substituted ethylenes is in agreement with the ideas encompassed by both the MO and resonance descriptions. Enamines, as amino-substituted alkenes are called, are vety reactive toward electrophilic species, and it is the p carbon that is the site of attack. For example, enamines are protonated on the carbon. Acrolein is an electrophilic alkene, as predicted, and the nucleophile attacks the P carbon. 

A poor leaving group can be made more reactive by coordination to an electrophilic species. Hydroxide is a very poor leaving group. Normally, alcohols therefore do not undergo direct nucleophilic substitution. It has been estimated that the reaction... 

A wide variety of electrophilic species can effect aromatic substitution. Usually, it is a substitution of some other group for hydrogen that is of interest, but this is not always the case. Scheme 10.1 lists some of the specific electrophilic species that are capable of carrying out substitution for hydrogen. Some indication of the relative reactivity of the electrophiles is given as well. Most of these electrophiles will not be treated in detail until Part B. Nevertheless, it is important to recognize the very broad scope of electrophiUc aromatic substitution. 

Scheme 10.1. Electrophilic Species Active in Aromatic Substitution...

The Friedel-Crafts reaction is a very important method for introducing alkyl substituents on an aromatic ring. It involves generation of a carbocation or related electrophilic species. The most common method of generating these electrophiles involves reaction between an alkyl halide and a Lewis acid. The usual Friedel-Crafts catalyst for preparative work is AICI3, but other Lewis acids such as SbFj, TiC, SnCl4, and BF3 can also promote reaction. Alternative routes to alkylating ecies include protonation of alcohols and alkenes. 

Similarly, carboxylic acid and ester groups tend to direct chlorination to the / and v positions, because attack at the a position is electronically disfavored. The polar effect is attributed to the fact that the chlorine atom is an electrophilic species, and the relatively electron-poor carbon atom adjacent to an electron-withdrawing group is avoided. The effect of an electron-withdrawing substituent is to decrease the electron density at the potential radical site. Because the chlorine atom is highly reactive, the reaction would be expected to have a very early transition state, and this electrostatic effect predominates over the stabilizing substituent effect on the intermediate. The substituent effect dominates the kinetic selectivity of the reaction, and the relative stability of the radical intermediate has relatively little influence. 

These singlet and triplet state species exhibit the important differences in chemical behavior to be expected. The former species, with their analogy to carbonium ions, are powerful electrophiles and the relative rates of their reaction with a series of substrates increases with the availability of electrons at the reaction center their addition reactions with olefins are stereospecific. Triplet state species are expected to show the characteristics of radicals i.e., the relative rates of additions to olefins do not follow the same pattern as those of electrophilic species and the additions are not stereospecific. 

The rate-determining step is the electrophilic aromatic substitution as in the closely related Friedel-Crafts reaction. Both reactions have in common that a Lewis acid catalyst is used. For the Blanc reaction zinc chloride is generally employed, and the formation of the electrophilic species can be formulated as follows ... 

Mechanistically it is an electrophilic aromatic substitution reaction. The electrophilic species (4—its exact structure is not known) is generated in a reaction of hydrogen cyanide and hydrogen chloride (gas) and a Lewis acid ... 

When lithiated, the ring strain of the three-membered heterocycle remains important, and this strain, combined with a weakening of the a-C-O bond, due to its greater polarization, make metalated epoxides highly electrophilic species [2], They react with strong nucleophiles (often the base that was used to perform the a-deprotonation) to give olefins following the elimination of M2O (Scheme 5.2, Path B), a process often referred to as reductive alkylation . 

Crosslinks result from the reaction of a bifunctional electrophilic species with DNA bases and imply a covalent link between two adjacent DNA strands which inhibits DNA replication. Primary targets within bases are N7 and 06 in guanine and N3 in cytosine. The initial lesions are removed by the suicide enzyme alkyltrans-ferase, whereas nucleotide excision repair is needed for frilly established crosslinks. 

Whereas bromine radicals (133) and succinimidyl radicals (134) react by the Sh2 mechanism at the tin center in tetraalkyltins, but not in alkyltin halides, alkoxyl radicals (135) and ketone triplets (136) react with alkyltin halides, but not tetraalkyltins this may reflect the conflicting, electronic demands of the radical reagents which, as electrophilic species, should be more reactive towards tetraalkyltins than alkyltin halides, but which would also tend to make use of a 5d orbital... 

As is the case in the tetrahedral mechanism, it is also possible for the electrophilic species to attack first, in which case it goes to the heteroatom. This species is most... 

The reactions of triphenylphosphazenyl derivatives with many other electrophilic species have been described. With sulphur tetrafluoride, sulphur imines are formed, possibly via the four-centred intermediate (24) ... 

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