Substitution in aromatic compounds

Both oxygen and nitrogen nucleophiles react more rapidly with fluoroaromatics than corresponding sulphur and carbon nucleophiles, in accordance with Hard-Soft Acid-Base principles [51]. It should be remembered, however, that the situation can become more complex with, for example, base catalysis, where the rate of the second stage becomes important under these rather unusual conditions, an order of replacement Br Cl F has been observed [52]. 

The second step may be rate-limiting in reactions of fluoroaryl systems with neutral amines [53]. Loss of halide ion from the intermediate complex is catalysed by base and is 

For orf/io-halonitrobenzenes, displacement of fluorine is more rapid than that of chlorine, due to lower steric requirements [55]. 

The foregoing discussion has outlined principles that can account for very wide differences in reactivities of the C—F bond. For example, while saturated perfluorocar-bons like polytetrafluoroethene are relatively inert to nucleophiles, at the other extreme are perfluoroisobutene, which reacts with neutral methanol, and perfluoro-l,3,5-triazine, which is hydrolysed in moist air. As a note of caution, great care should be taken with the systems that are very reactive to nucleophiles and correspondingly potentially very toxic, although there is no good correlation between toxicity levels and reactivity towards nucleophiles. More will be said about some of these systems in later chapters. 

Bunion, Nucleophilic Substitution at a Saturated Carbon Atom, Elsevier, Amsterdam, 1963. 

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Nucleophilic Substitution in Aromatic Compounds with Fluorinated Substituents (Russ ) Boiko, V N hv Sib Old Akad NaukSSSR 126-136 53 a c S... 

Nucleophilic Substitution in Aromatic Compounds with Fluorinated Substituents ... 

This synthesis shows how important electrophilic substitution in aromatic compounds is in industrial processes. It involves four separate such reactions as well as three nucleophilic aromatic substitutions. The chemistry of Chapters 22 and 23 is well represented here. 

Anodic oxidation of the nitroalkane anion to a radical may lead to dimerization [22], addition to unsaturated systems [23], or substitution in aromatic compounds [24] these reaactions are treated in Chapter 22. 

The mechanism composed of Eqs. (2), (3), (5), and (7) is observed typically for nuclear substitution in aromatic compounds, whereas side-chain substitutions, for instance, typically proceed according to Eqs. (2), (4), (6), and (8). (For a more thorough discussion of the reactions between radical cations and nucleophiles, the reader is referred to the rich literature on this subject [1,2].) Essentially the same mechanistic pattern is found in oxidative substitution driven by high valent inorganic ions [3-6]. 

Friedel-Crafts alkylation is an example of electrophilic substitution in aromatic compounds. The electrophile is formed in the reaction of an alkylhalide with a Lewis acid. The Lewis acid polarizes the alkylhalide molecule, making the hydrocarbon part of it bear a positive charge and thus become more electrophilic. 

Radical ipso attack and ipso substitution in aromatic compounds , Tiecco, M., Acc. Chem. Res., 1980, 13, 51. 

Applying the rules for substitution in aromatic compounds, write the graphic formulas of the compounds formed by the introduction of one and of two of the substituting groups when (a) C6H6C2H6, (6) CeHsOH, (c) CeHsBr, (d) C6H6NO2, and (e) CeHsCOOH are each nitrated and sulphonated. 

Substituents on benzene or benzenoid rings in fused pyridazines, i.e. in cinnolines and phthalazines, usually exhibit reactivity which is similar to that found in the correspondingly substituted fused aromatic compounds, such as naphthalene, and is therefore not discussed here. 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

Friedel-Crafts reactions involving electrophilic substitution of aromatic compounds have been reported on solid base catalysts such as thallium oxide and MgO. The rates of benzylation of toluene by benzyl chloride over MgO nanocrystals were found to be of the order CP-MgO > CM-MgO > AP-MgO.56 An important observation in the study was that x-ray diffraction of the spent catalyst... 

Anodic side chain substitution is a competing reaction to nuclear substitution of aromatic compounds. In side chain substitution, the first formed acidic radical cation is deprotonated at the a-carbon atom of an alkyl group to form a radical. This is further oxidized to a benzyl cation, which reacts with a nucleophile (Scheme 9, path d). The factors that influence the ratio of nuclear to side chain substitution have been described in 5.4.1. 

It has been shown that when nucleophilic aromatic photo-substitution reactions are carried out in non-deoxygenated solutions of aprotic solvents, such as DMSO and acetonitrile, destructive superoxide anions may be formed from aromatic radical anions. Such solvents are best avoided. There has been a review of mechanistic aspects of photo-substitutions of the cyano group in aromatic compounds. ... 

This awareness in a short time led to new homolytic aromatic substitutions, characterized by high selectivity and versatility. Further developments along these lines can be expected, especially as regards reactions of nucleophilic radicals with protonated heteroaromatic bases, owing to the intrinsic interest of these reactions and to the fact that classical direct ionic substitution (electrophilic and nucleophilic) has several limitations in this class of compound and does not always offer alternative synthetic solutions. Homolytic substitution in heterocyclic compounds can no longer be considered the Cinderella of substitution reactions. 

In a recent review, Tao etal. [34] describe the partial fluorination and the perfluorination of organics with particular emphasis on medically important compounds and pharmaceuticals. The selective electrofluorination (SEF) of olefins and active methylene groups is reviewed by Noel et al. [35] In the case of heterocycles, nuclear fluorination is known to be the predominant process. However, in aromatic compounds, nuclear substitution as well as addition proceeds simultaneously, leading to the formation of a mixture of products. The influence of solvents, supporting electrolytes, and adsorption on product yield and selectivity is summarized and evaluated. Dimethoxyethane is found to be a superior solvent for SEF processes. Redox mediators have been employed to minimize anode passivation and to achieve better current efficiencies. 

Electrophilic substitution reactions are those where an electrophile displaces another group, usually a hydrogen. Electrophilic substitution occurs in aromatic compounds. 

Substituted 1-fluoropyridinium triflates have been used for substitution of hydrogen by fluorine in aromatic compounds (Table 3).46"50 Thus benzene is transformed to fluorobenzene (56 % yield, l-fluoro-2,6-bis(methoxycarbonyl)pyridinium triflate), Af-ethoxycarbonylaniline gives Al-ethoxycarbonyl-2- and -4-fluoroaniline (60 and 27% yield, respectively, 1-fluoropyridinium triflate), and phenylurethane also gives the products of fluorination at position 2 (47%) and 4 (32%) of the aromatic ring [l-fluoro-2,6-bis(methoxycarbonyl)pyridinium triflate]. In the case of fluorination of anisole, 1-fluoropyridinium tetrafluoroborate gives 19% 2- and 17% 4-fluoroanisole.46... 

Thus, aryl-substituted antimony fluorides provide replacement of chlorine by fluorine atoms in aromatic compounds containing trichloromethyl and pentachloro- or dichlorotri-fluoroethyl groups. Their activity as fluorinating agents decreases in the order tetrafluoro(phenyl)-A5-stibane > trifluorodi(phenyl)-25-stibane >antimony(lIl) fluoride dill uorotri(phenyl)-/i.5-stibane. 

The replacement of the nitro group by fluorine in aliphatic compounds appears to be much less well known than in the aromatic series. The possibility of nitro group displacement in aromatic compounds was noted during the study of halide displacement in halo-substituted 2,4-dinitrobenzenes. The appearance of brown fumes and formation of traces of lower boiling products resulted in studying the exchange of the nitro group in 2,3,5,6-tetrachloro-l-nitroben-... 

In aromatic compounds carbon-13 shifts are largely determined by mesomeric (resonance) and inductive effects. Field effects arising from through-space polarization of the n system by the electric field of a substituent, and the influences of steric (y) effects on the ortho carbon nuclei should also be considered. Substituted carbon (C-l) shifts are further influenced by the anisotropy effect of triple bonds (alkynyl and cyano groups) and by heavy atom shielding. 

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