Theoretical studies on the reactivity of thiazole derivatives

The global and local quantum chemical reactivity descriptors of a series of thiazole derivatives substituted at 2, 4, and 5 positions with different groups including electron-donating and electron-withdrawing substituents, have been calculated at the B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of theory. The substituents have been selected to cover a wide range of electronic effects. Considering the calculated Fukui functions, thiazole derivatives are found to be suitable nucleophilic sites in the gas-phase. For the most substituents, it was observed that the calculated Fukui function values at the N-site are small in the case of electron-attracting substituents indicating a preferred N-site for hard reactions. In contrast, large values in case of electron-releasing groups indicate a preferred N-site for soft reactions. These two local descriptors predicted the reactivity of the electron-rich thiazoles and sequence to be 2-substituted thiazoles > 5-substituted thiazoles > 4-substituted thiazoles, where reactivity toward electrophilic attack at the pyridine nitrogen atom is enhanced by electron-donor substituents elsewhere in the molecule, due to resonance effect.