Drastic Deprotonation Reactivity Difference of 3-and 5-Alkylpyrazole Isomers, Their I2-Catalyzed Thermal Isomerization, and Telescoping Synthesis of 3,5-Dialkylpyrazoles: The "Adjacent Lone Pair Effect" Demystified

N-Protected 3-alkylpyrazoles are easily deprotonated by (BuLi)-Bu-n at the 5-position of the aromatic ring, while the 5-alkyl isomers are completely unreactive under the same conditions. Using computational analysis, we reveal that electron pair repulsion within the deprotonated anion is not the reason behind the lack of reactivity of 5-alkylpyrazoles. Instead, diminished pi-resonance and attractive electrostatic interactions within the pyrazole ring are responsible for the observed effect. A greener, telescoping alternative to the synthesis of 3,5-dialkylpyrazoles is presented.