Synthesis and protonation behavior of 26-membered oxaaza and polyaza macrocycles containing two heteroaromatic units of 3,5-disubstituted pyrazole or1-benzylpyrazole. A potentiometric and H-1 and C-13 NMR study

The synthesis and acid-base behavior of two series of 26-membered dioxatetr aamine and hexaamine heterocyclophanes containing two nuclei of either pyra zole (4a and 6a) or 1-benzylpyrazole (4b and 6b), respectively, are reporte d. 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 ga ve 4a;b in 75% and 84% yield, respectively. Condensation of 2a with diethyl enetriamine leads to a complex mixture containing imidazolidine isomers, wh ich 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 c rystallization was isolated as a pure compound in 80% yield and fully ident ified from analytical and H-1 and C-13 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 polyami ne 6b in 86% yield. Protonation constants of 4a,b and 6a,b have been determ ined by potentiometric methods in the pH 2-11 range, and their protonation sequences were established by a H-1 and C-13 NMR study in D2O at variable p H. For each compound, the number of protonation constants equals the number of nitrogens in the side chains. In the pH range studied, the pyrazole rin gs are not involved in protonation or deprotonation processes.