General survey of reactivity

Since the mid-1980s, the most significant aspect regarding pyrazoles reactivity concerns the publication of a series of papers dealing with gas phase studies and the enormous increase in the use of pyrazoles as ligands in metallo-organic and coordination chemistry. 

Nucleophilic attack at ring carbon occurs in benzenes only when electron-withdrawing substituents are present. Even with pyridine, only the strongest nucleophiles react. This is because the formation of the initial adduct (2) involves de-aromatization of the pyridine ring and, once formed, many such adducts tend to re-aromatize by dissociation (1 2). Benzo fusion decreases the loss in aromaticity for the formation of the adduct and thus quinoline (3) and especially acridine (4) react more readily with nucleophiles. 

Reaction with nucleophiles by deprotonation at a CH bond occurs in pyridine much more readily than in benzene. The reactivity order is y 3 a rather than y, a (3 because of lone pair lone pair repulsion in the a-deprotonated species (c/. discussion in Section 3.2.1.8). 

Extrapolation from benzene through pyridine to the diazines and then to the triazines and tetrazines delineates the main trends of azine chemistry. 

Isoxazoles are presently known to undergo hydrogen exchange, nitration, sulfonation, halogenation, chloroalkylation, hydroxymethylation, Vilsmeier-Haack formylation, and mercuration. The Friedel-Crafts reaction on the isoxazole nucleus has not yet been reported. 

Isoxazoles are susceptible to attack by nucleophiles, the reactions involving displacement of a substituent, addition to the ring, or proton abstraction with subsequent ring-opening. Isoxazolium salts are even more susceptible to attack by a variety of nucleophiles, providing useful applications of the isoxazole nucleus in organic synthesis. Especially useful is the reductive cleavage of isoxazoles, which may be considered as masked 1,3-dicarbonyl compounds or enaminoketones. 

2-Benzisoxazoles undergo electrophilic substitution in the benzo ring, but with nucleophiles the reaction occurs in the isoxazole moiety, often leading to salicylonitriles with 3-unsubstituted systems. The isomeric 2,1-benzisoxazoles are characterized by the ease with which they may be converted into other heterocyclic systems. 

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FULLY CONJUGATED RINGS REACTIVITY AT RING ATOMS 3.02.2.1 General Survey of Reactivity... 

General Survey of Reactivity of Substituents on Ring Carbon Atoms... 

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