Fused benzene rings substituted

Substituents on the benzene rings exert their usual influence on the orientation and ease of electrophilic substitution reactions. For example, further nitration (HN03-H2S04-S03) of nitroquino-lines occurs meta to the nitro group as shown in diagrams (593) and (594). Friedel-Crafts acylation of 8-methoxyquinoline succeeds (cf. 595) although this reaction fails with quinoline itself. 

A heterocyclic ring induces partial double-bond fixation in a fused benzene ring. Hence diazo coupling occurs at the 5-position of 6-hydroxyquinoline (596), and not at the 7-position. 

Amino groups on fused benzene rings in benzopyridines show basicity lower than aniline (initial proton addition occurs mainly on the hetero nitrogen atom) but are diazotized normally. Displacements of a diazonium group often occur under Gattermann but not under Sandmeyer conditions, probably because complexes are formed with Cu2+. 

However, a strongly electron-deficient heterocyclic ring can induce unusual reactivity as occurs for the 3-amino groups in phenazonium, phenoxazonium and phenothiazonium salts (597 Z = NR, O or S) which are important in dye chemistry. Thus, phenosafranine (592 Z=NPh, R = H) is converted by alkali into the imine (598 Y = NH) or, on more vigorous treatment, into the phenazone (598 Y = O). Methylene blue (592 Z = S, R = Me) on oxidation (K2Cr207-HCl) gives the imine (599 Y = NMe), and on treatment with alkali the oxo derivative (599 Y = O). 

In general, hydroxy groups on fused benzene rings undergo the expected reactions. O-Methylation is effected by diazomethane, methyl iodide or dimethyl sulfate. O-Alkylation is reversed by aluminum trichloride or tribromide in benzene or nitrobenzene. 

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In compounds with a fused benzene ring, electrophilic substitution on carbon usually occurs in the benzenoid ring in preference to the heterocyclic ring. Frequently the orientation of substitution in these compounds parallels that in naphthalene. Conditions are often similar to those used for benzene itself. The actual position attacked varies compare formulae (341)-(346) where the orientation is shown for nitration sulfonation is usually similar for reasons which are not well understood. 

Fused benzene rings are treated as substituents. Thus quinoline, for example, is considered as a substituted pyridine, albeit a very special and important one, and treated alongside other substituted pyridines in the discussion of its structure, reactivity and synthesis. Reactions of quinoline at positions 1-4 are considered as reactions at ring atoms, whilst reactions at positions 5-8 are regarded as reactions of the substituent . 

The polycyclic aromatic hydrocarbons such as naphthalene, anthracene, and phenan-threne undergo electrophilic aromatic substitution and are generally more reactive than benzene. One reason is that the activation energy for formation of the c-complex is lower than for benzene because more of the initial resonance stabilization is retained in intermediates that have a fused benzene ring. 

In addition to electrophilic attack on the pyrrole ring in indole, there is the possibility for additions to the fused benzene ring. First examine the highest-occupied molecular orbital (HOMO) of indole. Which atoms contribute the most What should be the favored position for electrophilic attack Next, compare the energies of the various protonated forms of indole (C protonated only). These serve as models for adducts formed upon electrophilic addition. Which carbon on the pyrrole ring (C2 or C3) is favored for protonation Is this the same as the preference in pyrrole itself (see Chapter 15, Problem 2)1 If not, try to explain why not. Which of the carbons on the benzene ring is most susceptible to protonation Rationalize your result based on what you know about the reactivity of substituted benzenes toward electrophiles. Are any of the benzene carbons as reactive as the most reactive pyrrole carbon Explain. 

The low yields of 6,6 -disubstituted-2,2 -bipyridincs recorded in Table I are probably the result of steric retardation of the adsorption of 2-substituted pyridines. This view is supported by the observation that 2-methylpyridine is a much weaker poison for catalytic hydrogenations than pyridine. On the other hand, the quinolines so far examined (Table II) are more reactive but with these compounds the steric effect of the fused benzene ring could be partly compensated by the additional stabilization of the adsorbed species, since the loss of resonance energy accompanying the localization of one 71-electron would be smaller in a quinoline than in a pyridine derivative. 

Because the reactive 4-position of pyrazole is substituted in indazole (benzo[b]pyrazole), substitution by electrophiles occurs by default in the 3-position initially, and then in the 5- and 7-positions of the fused benzene ring (ortho and para to the N-l). Anionic indazoles always halogenate at C-3 (84MI22). 

The dibenzopyranone ring system may be viewed as a chromone with an additional fused benzene ring and thus generally related to the antiasthmatic mediator release inhibitor cromolyn (see Chapter 11). Two dibenzopyranones have in fact been investigated for this indication in the clinic. Friedel-Crafts cyclization of the substituted cresyloxybenzoic acid (2-1) in sulfuric acid leads to the dibenzopyranone (2-2). The methyl group is then oxidized to a carboxylic acid by means of chromic acid. The acid is then converted to its sodium salt, xanoxate sodium (2-3) [2]. 

Some pK values are collected in Table 2. Thiones are ca. 2 pK units more acidic than the corresponding azinones. Fused benzene rings have little effect except in the 3-substituted isoquinoline series where partial bond fixation lowers the acidity. Additional aza substitution increases the acidity significantly. 

If the hetero ring is in the form of a pyridone, pyrone or A-oxide, or contains a strongly electron-donating substituent (OR or NR2), electrophilic substitution into the hetero ring can compete with substitution into a fused benzene ring. In some such compounds, substitution occurs entirely in the... 

Electrophilic substitution usually occurs preferentially in the aryl group. In compounds containing both an aryl group and a fused benzene ring, electrophiles usually attack the aryl group exclusively. 

A [Z ]-fused benzene ring would be expected to favor (3-substitution in the heterocyclic ring (53) over a-substitution (54) based on the expected cr-complex stability. 

The 7r-electron excessive character of pyrrole and indole renders both systems extremely susceptible to electrophilic attack and the fused benzene rings of carbazole also undergo electrophilic substitution more readily than does an unsubstituted benzene ring. In contrast, the 2/7-isoindole system only survives intact during electrophilic substitution reactions under the mildest of conditions and the system is more susceptible to [ 4 + 2] cycloaddition reactions than is pyrrole. 1,1-Disubstituted IH-isoindoles generally undergo nucleophilic addition-elimination reactions across the 2,3-bond or yield products derived from an initial electrophilic attack at the 2-position. 

Substitutents at the 4-position on pyNO do not affect the stoichiometry of the complex formed, nor does the single fused benzene ring of quinNO. However, substituents ortho to N can lead to complexes in which the coordination number of the metal is lower. Thus with 2-picNO, [Co(2-picNO)5 ][C104]2 can be obtained the cation has slightly distorted trigonal bipyramidal... 

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