Iodination of imidazoles

Many research workers have studied the kinetics and the mechanism of iodination of imidazole.06-100 The amphoteric character of the imidazole molecule and the existence of tautomeric equilibria make the reaction more complicated. In aqueous solution, at about pH 7, the rate equation consists of two terms, one suggesting reaction of the imidazole anion with I+ or IOH2+, and the other, involving dependence on the square of the imidazole concentration, indicating selfcatalysis by imidazole.98, 97 According to Ridd, the uncatalyzed term could also represent an internal rearrangement of an A-iodo to a O-iodo derivative, and the catalyzed reaction could be due to assisted proton loss in this transition state. 

The main kinetic features of the iodination of imidazole—which show a suggestive resemblance to those of the iodination of phenols102, 103—have been substantially confirmed by a study of Havinga and co-workers99,100 on the kinetics of iodination of histidine and some other imidazole derivatives. 

Vaughan and co-workers104 have studied the iodination of pyrazole. The kinetic features are similar to those of the iodination of imidazole. Also in this case, the rate could be separated into parallel uncatalyzed and base-catalyzed reactions and the mechanism proposed... 

The complexity of individual halogenation mechanisms has become clear in more recent years from the diverse isomer distributions observed under different reaction conditions. Quantitative product studies are beginning to make a welcome appearance, but kinetic studies are almost wholly lacking. The recent kinetic work on the iodination of imidazole may signal the onset of improvement in this aspect. On the theoretical side, much attention has been given to the several possible quantum mechanical approximations applicable to heterocyclic substitution. Here again the lack of ample quantitative... 

By far the greatest amount of study has been applied to the bromination and iodination of imidazoles and the benzologues. It is, however, becoming apparent that some of the definitive results may have been based on earlier incorrect assignment of structure, particularly in the case of 2-iodoimidazole. Subsequent discussion here will endeavour to examine some of these earlier results in the light of the presently available structural information. 

A detailed study of the kinetics of iodination of 2- and 4-methylimidazole (80JOC3108) showed that, like the iodination of imidazole, the reactions are base catalyzed, but whereas 2-methylimidazole (and imidazole) also undergoes uncatalyzed iodination, 4-methylimidazole does not. The relative rates for uncatalyzed iodination (imidazole 2-methylimidazole 4-methylimidazole) were 1 28 0 those for base-catalyzed iodination were 1 34 667. Further conclusions about the process of 2-iodination drawn from this study have been rendered dubious in the light of the reassignment of 2,4- as 4,5-diiodoimidazole <81JOC178l). 

As discussed earlier (see Section 7.2), electrophilic monochlorination, -bromination and -iodination of imidazoles and 1-substituted imidazoles is difficult because of the great propensity of the molecules to polyhalogenate. Methods have, however, been developed to achieve selective halogen introduction on all ring sites. Fluorination is a special case (see below). 

Many research workers have studied the kinetics and the mechanism of iodination of imidazole. The amphoteric character of the... 

Another interesting contribution to the problem of the intermediate in electrophilic aromatic substitutions is Grimison and Ridd s (1958, 1959) investigation of isotope effects in diazo-coupling and iodination of imidazole. Imidazole reacts in the form of its conjugate base (4) which couples with p-diazobenzenesulphonic acid at carbon atom 2 without an... 

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