Histidine and histamine are biogenic amines that are important in mammals. They both contain an imidazole nucleus, and their structures are closely related. (Trifluoromethyl)imidazoles are an interesting group of compounds that undergo hydrolysis to the corresponding carboxylic acids. Because of their structures and reaction pathway, they have the potential for use as covalent affinity labels in biological systems. The development of a facile photochemical method to introduce the CF3 group into the intact and substituted imidazole ring has greatly expanded the number of substituted CF3-imidazoles available for study. Substituted CF3-imidazoles hydrolyze via the E1cB mechanism (elimination-unimolecular-conjugate base). Thus, only the substituted imidazole anion can react. A single fluoride ion is lost in the slow step, forming a difluorodiazafulvene intermediate. In subsequent, fast steps, nucleophiles such as water, ammonia, or alcohol react with the difluorovinyl group to form acids, nitriles, or esters, respectively. The dissociation constants for anion formation (pK2), and rate constants for hydrolysis, ammonolysis, and alcoholysis (kr) are both highly sensitive to changes in substituents in the imidazole ring. The Dual Substituent Parameter (DSP) equation is a linear free energy relationship (LFER) used to correlate changes in substituents with changes in reactivity. A DSP analysis showed that pK2 and kr for the hydrolysis of 2-CF3-imidazoles are influenced more by inductive effects than by resonance effects. The same was true for kr for 4-CF3-imidazoles. Extended Huckel molecular orbital calculations provided theoretical support for the experimental observations that 4-CF3-imidazole reacts faster than 2-CF3-imidazole and that electron-donating substituents accelerate the hydrolysis reaction. The LFER analysis showed that the unusual and interesting aspect of this reaction is that electron-withdrawing substituents are required to lower pK2 and effect dissociation at lower pH, but electron-donating substituents are required to enhance the rate of hydrolysis relative to the unsubstituted CF3-imidazoles. These LFERs allow the design of molecules that ionize at biological pH and possess the reactivity necessary to bind covalently to receptor sites.

Kinetics and mechanism of hydrolysis of substituted (trifluoromethyl)imidazoles

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.