Ring-trifluoromethylated imidazoles show the unique property of losing hydrogen fluroride above pH8 to form metastable difluoroduzafulvenes, which then react with any available nucleophile to form new covalent bonds. Such intermediates, derived from trifluoromethylhistamine or histidine, may be able to serve as covalent affinity labels for specific binding sites, both in vitro in vivo. It would be desirable, therefore, to have available a series of trifluoromethyl analogues with a range of reactivities, and to be able to correlate reactivity with some substituent parameter. Our discovery of a simple photochemical method for the trifluoromethylation of imidazoles has made available a large series of analogues for study. We have now found that the reactivities of some members of the group can be correlated with the special electronic effects of certain substituents (capable of hyperconjugation or back-bonding). Computer analysis of reactivity data for a series of trifluoromethylimidazoles has provided a linear free energy relationship in which log k-r correlated with both inductive and resonance components of the respective substituents. According to computer-based predictions, the fluoro group would provide the ideal combination of acidity and reactivity under physiological conditions. We have, therefore, developed procedures for sequential photochemical introduction of fluorine and trifluoromethyl into imidazoles and have verified the predicted reactivities. We are now involved in the preparation of peptide hormones containing these substituents. Photochemical introduction of the trifluoromethyl group has been found practical for more complex imidazoles and studies are under way for the synthesis of the trifluoromethyl analogue of the anti-ulcer drug, cimetidine.
