Structural analogues of thyronamines. Computational ¹H and ¹³C NMR study of 4-[4-(2-aminoetoxy)phenoxy]aniline – a new structural analogue of thyronamines

Endogenous thyronamines are known metabolites of L-thyroxine formed by deiodination and decarboxylation reactions. New structural analogues of thyronamines are actively studied with a view to expand the range of available compounds in this series, to identify the features of their biological action, especially their effects on the central nervous system, cardiovascular system, and metabolism. Structural features of thyronamines’ synthetic analogues in solutions can be investigated using the possibilities of complementary experimental and computational NMR spectroscopy.

Experimental and molecular modeling data on chemical shifts of ¹H and ¹³C nuclei are presented for the 4-[4-(2-aminoethoxy)phenoxy]aniline (APA) dihydrochloride, that is a new structural analogue of thyronamine. In our study we treat two structural models of the APA – its protonated form [H-APA-H]²⁺ and neutral dihydrochloride APA·2HCl. The intramolecular dynamics of the key structural fragments of them were studied using semiempirical as well as DFT methods. Chemical shifts of the ¹H and ¹³C nuclei were estimated for the basic conformers of [H-APA-H]²⁺ and APA·2HCl models. Nonspecific solvation with DMSO was taken into account within the polarized continuum model. Calculated chemical shifts of the ¹H and ¹³C nuclei are in good agreement with the experimental ones obtained for 4-[4-(2-aminoethoxy)phenoxy]aniline dihydrochloride in DMSO-d₆ solution. The procs and cons of considered structural models are discussed.