Enhancer electrophilic aromatic substitution

Acid-Strengthening ring substituents also retard electrophilic, and enhance nucleophilic, aromatic substitution. Conversely, the acid-weakening groups accelerate electrophilic, and retard nucleophilic, aromatic substitution. 

The effect of monofluorination on alkene or aromatic reactivity toward electrophiles is more difficult to predict Although a-fluonne stabilizes a carbocation relative to hydrogen, its opposing inductive effect makes olefins and aromatics more electron deficient. Fluorine therefore is activating only for electrophilic reactions with very late transition states where its resonance stabilization is maximized The faster rate of addition of trifluoroacetic acid and sulfuric acid to 2-fluoropropene vs propene is an example [775,116], but cases of such enhanced fluoroalkene reactivity in solution are quite rare [127] By contrast, there are many examples where the ortho-para-dueeting fluorine substituent is also activating in electrophilic aromatic substitutions [128]... 

In the preceding reactions, the arylation was regioselective with an outcome similar to electrophilic aromatic substitution. However, with simple benzene derivatives, mixtures of biaryl derivatives have been obtained (Scheme 10.53).85 The role of silver trifluoroacetate in these arylations was crucial and, as proposed by the authors, this silver salt could enhance the reactivity and reoxidize Pd species. 

Electron-donating groups have a dual effect rate enhancement owing to electronic factors, as expected for electrophilic aromatic substitution, and a rate deerease as a result of steric and transport restrictions. Even the size of the methyl group in toluene is sufficient to compensate for the increased electron density on the aromatie nucleus, as shown by competition kinetics (benzene/toluene 1 1.3 for TS-I/H2O2, 1 10 for trifluoroperacetic acid) [2,27]. The nuclear reactivity trend of alkylbenzenes was in the sequence toluene > /7-xylene > ethylbenzene > /7-methylethylbenzene, in accordance with increasing molecular size... 

Small cyclophanes generally exhibit an enhanced reactivity compared to the constituent arenes. In [2n]cyclophanes, for example, electrophilic aromatic substitution is facilitated by transannular interactions with the n-basic second deck furthermore, Lewis-basic substituents direct a substitution in the second ring predominantly to the pseudogeminal position. Strain relief plays an important role in reactions like catalytic hydrogenation, cycloadditions, and cleavage or rearrangement of bridges. 

Finally, Loeb and coworkers investigated the bromination of m-nitrotoluene at elevated temperatures (170-230 °C) and pressures (up to 15 bar) to synthesize the corresponding benzyl bromide via side-chain bromination [26-28] (which, of course, is not electrophilic aromatic substitution in the true sense, as predominantly regarded in this chapter). In comparison with the macroscopic process, the reaction could be drastically accelerated in microreactors, thus enhancing the space-time yield by a factor of 18. A further process intensification was achieved by running the... 

Electrophilic Aromatic Substitution. Micellar SDS has been used as a reaction medium for the chlorination and bromlnatlon of alkyl phenyl ethers T gjj(j phenol by several halogenatlng agents (eq 1). Compared to reactions in H2O alone, theparar.ortho product ratio increased for pentyl, nonyl, and dodecyl phenyl ether, and decreased for anlsole. Enhanced ortho relative to para substitution was obtained with phenol. In each case the observed regios-electivity derived at least in part from alignment of the substrate at the micelle-H20 interface and resultant differential steiic shielding of the para and ortho positions by the micelle superstructure. 

The reaction was proposed to follow either an electrophilic aromatic substitution or general cross-coupling pathway. To ascertain whether a cross-coupling pathway was followed experiments involving the use of Cul as co-catalyst were carried out. No enhancement in reaetivity or selectivity after using Cul as the co-catalyst suggested that the possible mechanistic pathway followed is the eleetrophilic aromatic substitution rather than eross-coupling. 

Recently, it has been shown that 3-pyridinecarboxal-dehyde undergoes the same reaction in weaker acid solutions of sulfuric acid with H, values around -9. NMR analysis definitively established that the dication shown below is generated under the reaction conditions, and the two positive charges enhance the electrophilic aromatic substitution with benzene. 

Recently37, the importance of CT complexes in the chemistry of heteroaromatic N-oxides has been investigated in nucleophilic aromatic substitutions. Electron acceptors (tetracyanoethylene and p-benzoquinones) enhance the electrophilic ability of pyridine-N-oxide (and of quinoline-N-oxide) derivatives by forming donor-acceptor complexes which facilitate the reactions of nucleophiles on heteroaromatic substrates. 

The reaction of toluene-2,4-diisocyanate with chlorine to l-chloromethyl-2,4-diisocyanatobenzene was carried out in a falling-film microstructured reactor with a transparent window for irradiation [264]. There are two modes of reaction. The desired radical process proceeds with the photoinduced homolytic cleavage of the chlorine molecules, and the chlorine radical reacts with the side chain of the aromatic compound. At very high chlorine concentrations radical recombination becomes dominant and consecutive processes such as dichlorination of the side chain may occur as well. Another undesired pathway is the electrophilic ring substitution to toluene-5-chloro-2,4-diisocyanate, promoted by Lewis acidic catalysts in polar solvents at low temperature. Even small metallic impurities probably from corrosion of the reactor material can enhance the formation of electrophilic by-products. 

That electron-donating substituents, which increase the electron density of the aromatic ring, enhance the reactivity of the ring towards electrophiles, directing substitution to the ortho and para positions... 

A mechanism for the final step is shown below. Overall, this step constitutes two subsequent electrophUic aromatic substitution reactions, resulting in the formation of two new B-C bonds. Addition of aluminum trichloride, a Lewis acid, serves to enhance the electrophilicity of the boron by forming a complex with one of the chlorine atoms. The boron is then attacked by one of the pendant arenes, with subsequent loss of AlCLt and formation of a resonance-stabilized sigma complex (several, but not all, of the many resonance structures are shown). Deprotonation with AlCl4 restores aromaticity, giving a neutral intermediate. An identical sequence of mechanistic steps (complexation with AICI3, attack of the arene, loss of AlCLt and deprotonation) results in fte formation of the second B-C bond, thus producing compound 3. 

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