Aromatic Substitutions and Additions

As has already been mentioned in Chap. 2, aromatic substitution was the first object of theoretical treatment of chemical reactivity. The reactivity indices of Chap. 6 have also been first applied to the aromatic substitution. Since existing papers and reviews gj-e available for the purpose of verifying the usefulness of the indices,/r and Sr, only a few supplementary remarks are added here. 

These indices were initially used in the frame of Hiickel MO method. But the theory has been shown to be valid also in more elaborate methods 

A ten 7t electron heterocycle, imidazo [/,2-a] Pyridine was studied by Paudler and Blewitt The protonation occurred at Ni, which was calculated to have a total n electron density less than N4 (Fig. 

They calculated /) distribution to find that this is larger at Ni than N4 (Fig. 7.18b). Bromination took place at C3 where both qr and /r are largest. 

One example showing a serious discrepancy of the frontier electron method was reported by Dewar This is 10j9-borazaphenanthrene, 

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Oxazoline-directed aromatic substitution and addition reactions provide synthetic chemists with powerful tools for the construction of complex aromatic compounds. Since the last authoritative review by Meyers, these technologies have matured and found widespread applications in organic synthesis. While there has been somewhat limited methodological research in this area in the intervening years, one particularly exciting new development is the diastereoselective ortho-metalations directed by chiral oxazolines. Sections 8.3.9.1-8.3.9.3 will discuss these new developments as well as new synthetic applications of these reactions. 

As mentioned above, carbocations feature in many reactions, such as nucleophilic substitution (Sjjl) and elimination (El), additions of electrophiles to double and triple bonds, electrophilic aromatic substitution, and additions to carbonyl compounds and enolate chemistry (albeit in masked form). 

Previously (10,13), the authors succeeded in selective syntheses of 4-hydroxybenzoic acids from phenols and carbon tetrachloride, using 3-cyclodextrin (3-CyD) as catalyst. With the use of 3-CyD catalyst, a side reaction, carboxylation at the ortho-position, was largely suppressed, and 4-hydroxybenzoic acids were synthesized in selectivity larger than 95 %. In addition, various aromatic substitution and addition reactions were achieved in virtually 100 % selectivity and high yields in the presence of CyDs as catalyst (9-13). Selective catalyses involve regioselectivity, regulation of molecular sizes of intermediates and products, and/or protection of unstable products (9-13). 

II. The Structure of Mesomeric Systems ibid., 3350. A Molecular Orbital Theory of Organic Chemistry. III. Charge Displacements and Elearomeric Substituents ibid., 3353. A Molecular Orbital Theory of Organic Chemistry. IV. Free Radicals ibid., 3355. A Molecular Orbital Theory of Organic Chemistry. V. Theories of Reactivity and the Relationship Between Them ibid., 3357. A Molecular Orbital Theory of Organic Chemistry. VI. Aromatic Substitution and Addition. 

In the first century of "organic" chemistry much attention was given to the structures of carbogens and their transformations. Reactions were classified according to the types of substrates that underwent the chemical change (for example "aromatic substitution," "carbonyl addition," "halide displacement," "ester condensation"). Chemistry was taught and learned as transformations characteristic of a structural class (e.g. phenol, aldehyde) or structural subunit... 

Substituent effect, additivity of, 570 electrophilic aromatic substitution and, 560-563 summary of. 569 Substitution reaction, 138 Substrate (enzyme), 1041 Succinic acid, structure of, 753 Sucralose, structure of. 1006 sweetness of, 1005 Sucrose, molecular model of. 999 specific rotation of, 296 structure of, 999 sweetness of, 1005 Sugar, complex, 974 d, 980 L, 980... 

The mechanism for electrophilic aromatic substitution is addition-elimination. Using these working hypotheses, Mills and Nixon explained the regioselectivity of electrophilic substitution in 5-hydroxyindan versus 6-hydroxytetralin. 

The success of this reaction was ascribed to the solubility of the chlorozinc intermediate, whereas other chloramine-T derivatives (e.g. the sodium salt) are insoluble. An alternative non-nitrene pathway was not eliminated from consideration. On the other hand, no aromatic substitution or addition, characteristic of a free sulphonyl nitrene (see below), took place on treatment of jV,lV-dichloromethanesulphonamides with zinc powder in benzene in the cold or on heating. The only product isolated was that of hydrogen-abstraction, methanesulphonamide 42>, which appears to be more characteristic of the behaviour of a sulphonyl nitrene-metal complex 36,37). Photolysis of iV.iV-dichloromethanesulphonamide, or dichloramine-B, or dichloramine-T in benzene solution led to the formation of some unsubstituted sulphonamide and some chlorobenzene but no product of addition of a nitrene to benzene 19>. 

The quantitative treatment of the electron-transfer paradigm in Scheme l by FERET (equation (104)) is restricted to the comparative study of a series of structurally related donors (or acceptors). Under these conditions, the reactivity differences due to electronic properties inherent to the donor (or acceptor) are the dominant factors in the charge-transfer assessment, and any differences due to steric effects are considered minor. Such a situation is sufficient to demonstrate the viability of the electron-transfer paradigm to a specific type of donor acceptor behavior (e.g. aromatic substitution, olefin addition, etc.). However, a more general consideration requires that any steric effect be directly addressed. 

Albini and co-workers were able to trap radicals by alkenes giving rise to two processes, namely the radical olefin addition-aromatic substitution and the addi-... 

Two other important modes of substitution require mention here. They are the SNAr and elimination-addition reactions. Actually, it is sometimes difficult to distinguish between true aromatic nucleophilic substitutions and addition-elimination processes. The second group involves pyridyne intermediates (Scheme 53). Both of these reaction types are discussed fully under substituent reactions (Chapter 2.06). 

Eclipsed conformation, 7, 254 Electrocyclic reactions, 341, 344-348 Electrol ic oxidation, 307 Electrolytic reduction, 307 Electromeric effect, 24 Electron configuration, 3 Electron density, 21, 26, 29, 393 Electron-donating groups, 23, 26 addition to 0=C and, 183 addition to 0=0 and, 205, 206 aromatic substitution and, 153, 158 pinacol change and, 115 Electronegativity, 21, 22, 95 Electrons, lone pair, 10, 72 Electron spin, paired, 2, 308 Electron-withdrawing groups, 23 acidity and, 59, 61, 62, 272... 

The fluorination of other activated aromatic compounds, such as anisole and phenol, undergo monofluorination mainly in the ortho and para positions, whereas the fluorination of deactivated aromatics, such as nitrobenzene, trifluoromethylbenzene and benzoic acid, give predominantly the corresponding meta fluoro-derivatives which is consistent with a typical electrophilic substitution process. Also, fluoro-, chloro- and bromo-benzenes are deactivated with respect to benzene itself but are fluorinated preferentially in the ortho and para positions [139]. At higher temperatures, polychlorobenzenes undergo substitution and addition of fluorine to give chlorofluorocyclohexanes [136]. 

The gain in stabilization attendant on regeneration of the aromatic ring is sufficiently advantageous that this, rather than combination of the cation with Y0, normally is the favored course of reaction. Herein lies the difference between aromatic substitution and alkene addition. In the case of alkenes there usually is no substantial resonance energy to be gained by loss of a proton from the intermediate, which tends therefore to react by combination with a nucleophilic reagent. 

Substituted 1,2,3-triazole 1-oxides 448 have been reported to undergo electrophilic and nucleophilic aromatic substitution and are subject to debromination, proton-metal exchange, and halogen-metal exchange followed by electrophilic addition. Transmetallation and cross-coupling have not been described. 3-Substituted 1,2,3-triazole 1-oxides 448 can be proton-ated or alkylated at the O-atom and they can be deoxygenated and deal-kylated. The individual reactions are described in Section 4.2.7.1-4.2.7.14. 

Liquid-phase fluorination of alkyl-substituted anisole derivatives with xenon difluoride depends strongly on the structure of the aromatic molecule. Substitution and addition processes were observed in the case of the methyl derivative, while beside substitution of the hydrogen atom, dealkylation was also established with l-methoxy-4-J-butyl benzene89,90 (Scheme 29). 

Aromatic compounds undergo many reactions, but relatively few reactions that affect the bonds to the aromatic ring itself. Most of these reactions are unique to aromatic compounds. A large part of this chapter is devoted to electrophilic aromatic substitution, the most important mechanism involved in the reactions of aromatic compounds. Many reactions of benzene and its derivatives are explained by minor variations of electrophilic aromatic substitution. We will study several of these reactions and then consider how substituents on the ring influence its reactivity toward electrophilic aromatic substitution and the regiochemistry seen in the products. We will also study other reactions of aromatic compounds, including nucleophilic aromatic substitution, addition reactions, reactions of side chains, and special reactions of phenols. 

Notice the symmetry in this mechanism. Benzyne is formed from an ortho carbanion and it gives an ortho carbanion when it reacts with nucleophiles. The whole mechanism from bromobenzene to aniline involves an elimination to give benzyne followed by an addition of the nucleophile to the triple bond of benzyne. In many ways, this mechanism is the reverse of the normal addition-elimination mechanism for nucleophilic aromatic substitution and it is sometimes called the elimination-addition mechanism, the elimination step... 

Because the elementary reactions of cationic alkene polymerizations are directly related to the organic chemistry of carbocations, Chapter 2 will investigate electrophilic additions to double bonds, nucleophilic substitution, electrophilic aromatic substitution, and elimination reactions. 

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