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

Abstract

N-Protected 3-alkylpyrazoles are easily deprotonated by (n)BuLi 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 π-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.

Tuning the structure and solubility of nanojars by peripheral ligand substitution, leading to unprecedented liquid–liquid extraction of the carbonate ion from water into aliphatic solvents

“…4-Hydroxypyrazole, 35 3-hydroxypyrazole, 36 4-fluoropyrazole, 37 4-chloropyrazole, 38 4-bromopyrazole, 38 4-iodopyrazole, 29 4-nitropyrazole, 39 4-formylpyrazole, 40 3-formylpyrazole, 41 pyrazole-4-sulfonic acid, 42 3,5-diethylpyrazole, 43 3(5)-n-butyl-5(3)-n-hexylpzH, 44 3,5-di-tert-butylpyrazole, 45 3,5-bis(trifluoromethyl)pyrazole, 46 3,5-diphenylpyrazole, 47 4-phenylpyrazole, 48 4-nbutylpyrazole, 49 4-(3-hydroxypropyl)pyrazole 50 and 3(5)-n-alkylpyrazoles 51 (alkyl = Me, Et, Pr, Bu, Oct) are prepared according to published procedures. All other commercially available chemicals are used as received.…”

Solvent- and catalyst-free, quantitative protection of hydroxyl, thiol, carboxylic acid, amide and heterocyclic amino functional groups

“…The utility of a same-pot protection step in telescoping syntheses had been illustrated with the one-pot synthesis of 3-alkyl-and 3,5-dialkylpyrazoles. 18,19 As the first step in the protection mechanism is a proton transfer, substrates with increased acidity are expected to be protected more readily by DHP, whereas less acidic substrates are expected to have reduced reactivity. A series of substrates, with pK a values ranging from 4.2 to 27, have been tested (Table 1).…”