Synthesis and protonation behavior of 26-membered oxaaza and polyaza macrocycles containing two heteroaromatic units of 3,5-disubstituted pyrazole or 1-benzylpyrazole. a potentiometric and ¹H and ¹³C NMR study

Abstract

The synthesis and acid−base behavior of two series of 26-membered dioxatetraamine and hexaamine heterocyclophanes containing two nuclei of either pyrazole (4a and 6a) or 1-benzylpyrazole (4b and 6b), respectively, are reported. Dipodal (2 + 2) condensations of 3,5-pyrazoledicarbaldehyde 2a or its 1-benzyl derivative 2b with 1,5-diamino-3-oxapentane afford in both cases the stable Schiff bases 3a,b in 90% yield, which after reduction with NaBH₄ gave 4a,b in 75% and 84% yield, respectively. Condensation of 2a with diethylenetriamine leads to a complex mixture containing imidazolidine isomers, which was reduced in situ to afford 6a in 30% yield. Condensation of 2b with the same amine gave the stable diimidazolidine derivative 5b, which after crystallization was isolated as a pure compound in 80% yield and fully identified from analytical and ¹H and ¹³C NMR data as a constitutional isomer with both imidazolidine rings located at the side of the pyrazole closer to the benzylic substituents. Reduction of 5b with NaBH₄ afforded the polyamine 6b in 86% yield. Protonation constants of 4a,b and 6a,b have been determined by potentiometric methods in the pH 2−11 range, and their protonation sequences were established by a ¹H and ¹³C NMR study in D₂O at variable pH. For each compound, the number of protonation constants equals the number of nitrogens in the side chains. In the pH range studied, the pyrazole rings are not involved in protonation or deprotonation processes.