Ring-activating substituents

Any substituent whose atom attached to the benzene contains a lone pair of electrons is ortho-para directing (but not necessarily a ring activator). Substituents without a lone pair on the atom attached to the ring are likely meta directors (with the exception of alkyl groups and aromatic rings, which turn out to be ortho-para directors). 

Electrophilic aromatic substitutions The chemistry of pyrimidine is similar to that of pyridine with the notable exception that the second nitrogen in the aromatic ring makes it less reactive towards electrophilic substitutions. For example, nitration can only be carried out when there are two ring-activating substituents present on the pyrimidine ring (e.g. 2,4-dihydroxypyrimidine or uracil). The most activated position towards electrophilic substitution is C-5. 

Nitro groups in aromatic rings activate substituents in ortho and para positions for nucleophilic displacements. The nucleophile here is a chloride anion that replaces fluorine. Of the live nitro groups, those in both ortho and para positions to fluorine activate fluorine for nucleophilic displacement very strongly, so that even a relatively weak nucleophile like chloride replaces fluorine under very mild conditions. Compound R is chloropentanitrobenzene [37],... 

Salicylaldehydes can be condensed, by base or acid catalysis, with ketones that have an a-methylene. When base catalysis is used, the intermediate hydroxy-chalcones can be isolated, but overall yields are often better when the whole sequence is carried out in one step, using acid. It is important to note that because this route does not rely upon an electrophilic cychsation onto the benzene ring, 1-benzopyryliums free from benzene ring (activating) substituents can be produced. 

The presence of activating substituent on the carbocyclic ring can, of course, affect the position of substitution. For example, Entries 4 and 5 in Table 14.1 reflect such orientational effects. Entry 6 involves using the ipso-directing effect of a trimethylsilyl substituent to achieve 4-acetylation. 

When activating substituents are present in the benzenoid ring, substitution usually becomes more facile and occurs in accordance with predictions based on simple valence bond theory. When activating substituents are present in the heterocyclic ring the situation varies depending upon reaction conditions thus, nitration of 2(177)-quinoxalinone in acetic acid yields 7-nitro-2(177)-quinoxalinone (21) whereas nitration with mixed acid yields the 6-nitro derivative (22). The difference in products probably reflects a difference in the species being nitrated neutral 2(177)-quinoxalinone in acetic acid and the diprotonated species (23) in mixed acids. 

Conflicting reports on the nitration of phenazine have appeared, but the situation was clarified by Albert and Duewell (47MI21400). The early work suggested that 1,3-dinitroph-enazine could be prepared in 66% yield under standard nitration conditions however, this proved to be a mixture of 1-nitrophenazine and 1,9-dinitrophenazine (24). As with pyrazines and quinoxalines, activating substituents in the benzenoid rings confer reactivity which is in accord with valence bond predictions thus, nitration of 2-methoxy- or 2-hydroxy-phenazine results in substitution at the 1-position. 

Some of the most powerful activating substituents are those in which an oxygen atom is attached directly to the ring. These substituents include the hydroxyl group as well as alkoxy and acyloxy groups. All are ortho, para directors. 

Section 12.15 When two or more substituents aie present on a ring, the regioselectivity of electrophilic aiomatic substitution is generally controlled by the directing effect of the more powerful activating substituent. 

One complication of the Pictet-Spengler condensation of benzylisoquinolines 24 is regiochemical control in the closure of ring C when activating substituents are present on the D ring. Experimentally, the ring-closure reaction yields predominantly the 10,11-disubstituted product 23 rather than the 9,10-disubstituted product 25. ... 

R Substituents affect the reactivity of the aromatic ring. Some substituents activate the ring, making it more reactive than benzene, and some deactivate the ring, making it less reactive than benzene. In aromatic nitration, for instance, an -OH substituent makes the ring 1000 times more reactive than benzene, while an —N02 substituent makes the ring more than 10 million times less reactive. 

Bromination of 136 in methanol gave the 3-bromo derivative, identical with the product of Sandmeyer reaction of the 3-diazonium salt. When the reactive 3-position was blocked, electrophilic bromination would not take place (66JOC265). Chlorination appears to occur by addition [83AHC(34)79], and perhalides are known [84MI25 90AHC(47)1]. Activating substituents are able to induce some bromination in the pyridine ring. 

There has been quite thorough study of 3,5-hexadienyl acrylates, where the ester functions both as part of the link and an activating substituent. The reaction tends to be quite slow, even though at first glance it would appear to encounter little strain. The cis ring juncture is favored by 9 1. 

In the case of electron-rich aromatic rings, for example, 472 it is possible to take advantage of the activating substituents to effect a Pictet-Spengler reaction to prepare the tetrahydroisoquinoline derivative 473 as shown in Scheme 7.153. ... 

The attachment to the pyridine ring of at least two activating substituents is required for C-nitrosation. The monoaminopyridines undergo IV-nitrosation to yield pyridinones and this reaction accompanies C-nitrosation (Scheme 39) (75RCR823). 

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