Reactivity values azoles

With the aid of the Bronsted equation [Eq. (15)] the reactivities of simple azoles or benzazoles may be predicted from a knowledge of their pKa values. While this equation was derived for N-methylation reactions using solvents such as DMSO and dimethyl sulfate, it can be applied to estimate nucleophilicity toward other alkylating agents in various solvents provided that (a) the Bronsted / values for the new systems are similar to the old one, and (b) that steric factors are unimportant. The foregoing discussion serves as a guide to indicate when such limitations apply. 

The positional reactivity order in thiazole is again the expected one. However, the magnitudes of the different from those in Scheme 7.12. The most probable cause for this is that the azoles are very susceptible to demands for resonance stabilization of the transition state for a particular reaction. This is not unexpected, because the reactivity of the azoles is the product of two opposing electronic effects from the heteroatoms, which are each large. A small alteration in the demand for resonance in a particular reaction may dramatically upset this balance. 

There have been many molecular orbital calculations performed on the azoles, the majority of them directed toward determining factors other than their electrophilic reactivities. In view of the wide range of with activation or deactivation depending upon the reaction studied, it is clear that calculations are unlikely to be able to provide more than the positional order of reactivities since they are unable to take account of the structure of a given transition state. The positional orders can, however, be much more simply obtained by application of a few elementary principles, as follows. 

On comparison of simple 1,2,4-triazoles with benzene, replacement of CH=CH in the latter by NH enhances reactivity towards electrophilic reagents but two replacements of CH by N act in the opposite direction (see Section 4.02.1.1). Comparison with other azoles is of greater heuristic value still (B-76MI41200). 

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