Electrophiles halogen substituents

Returning to Table 12 2 notice that halogen substituents direct an incoming electrophile to the ortho and para positions but deactivate the ring toward substitution Nitration of chlorobenzene is a typical example of electrophilic aromatic substitution m a halobenzene... 

Electrophilic aromatic substitution (Section 12.14) Halogen substituents are slightly deactivating and ortho, para-directing. Br... 

The hydroxyl group is a strongly activating, ortho- and para-directing substituent in electrophilic aromatic substitution reactions (Section 16.4). As a result, phenols are highly reactive substrates for electrophilic halogenation, nitration, sulfonation, and lTiedel-Crafts reactions. 

The two isomeric possibilities are 1,2- and 2,1-benzisoxazole. Both are preferentially halogenated by electrophilic halogen in the homocyclic ring, initially in the 5-position, although substituents can modify this behavior [67AHC(8)277]. Nucleophiles attack the heteroring (84MI26). 

Both electrophilic and nucleophilic reactions can generate halogenopur-ines with differences in regioselectivity dependent on substituents and on the nature of the substrate (anion, neutral molecule, or cation). In the neutral molecule nucleophilic displacements occur in the order 2 > 4 > 6 in the anion the imidazole ring may be sufficiently 7r-excessive for attack to occur at C-2, and the nucleophilic substitution order becomes 4 > 6 > 2. Strong electron donors are usually necessary to promote 2-halogenation by electrophilic halogen sources. 

We may ask How does Y know which side will give the more stable carbocation As in the similar case of electrophilic aromatic substitution (p. 681), we invoke the Hanunond postulate and say that the lower energy carbocation is preceded by the lower energy transition state. Markovnikov s rule also applies for halogen substituents because the halogen stabilizes the carbocation by resonance ... 

In Sect. 11.4, we examined hydrolytic attack at sp3 C-atoms rendered more electrophilic by the presence of one or more halogen substituents. In a logical follow-up, the present section presents the hydrolysis of Mannich bases [78], L e., compounds that contain the X-CH2-N moiety, where an sp3 C-atom is made more electrophilic by the presence of two flanking heteroatoms, one of which is an N-atom. 

Because halogenation involves electrophilic attack, substituents on the double bond that increase electron density increase the rate of reaction, whereas electron-withdrawing substituents have the opposite effect. Bromination of simple alkenes is an extremely fast reaction. Some specific rate data are tabulated and discussed in Section 6.3 of Part A. 

It has been demonstrated in CHEC-II <1996GHEC-II(7)431> that halogen substituents as well as other good leaving substituents can be readily replaced by carbon nucleophiles, for example, cyanide ion or active methylene compounds. Also, direct cyanation of l-phenylpyrazolo[3,4-i/]pyrimidine was demonstrated. Since then, reactivity toward carbon nucleophiles has not received much attention. However, a few interesting reactions with carbon electrophiles have been reported in the last few years. Thus, reacting 154 with 155 affords 156 (Equation 9) <2002BML1687>. 

In examining data on selectivity of electrophilic substitution, especially halogenations, one is well advised to examine the conditions under which the data were collected, owing to the fact that thiophenes bearing halogen substituents at the a-positions are often extremely subject to acid catalyzed rearrangements to the thermodynamically more stable isomers (68JOC2902). 

In case of halogen substituents, the inductive effect is more important than the resonance effect in deactivating the ring. However, once electrophilic substitution does occur, resonance effects are more important than inductive effects in directing substitution. 

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