A comparative study between para‐aminophenyl and ortho‐aminophenyl benzothiazoles using NMR and DFT calculations

Abstract

Ortho-and para-substituted aminophenyl benzothiazoles were synthesized and characterized using NMR spectroscopy. A comparison of the proton chemical shift values reveals significant differences in the observed chemical shift values for the NH protons indicating the presence of a hydrogen bond in all ortho-substituted compounds as compared to the para compounds. The presence of intramolecular hydrogen bond in the ortho amino substituted aminophenyl benzothiazole forces the molecule to be planar which may be an additional advantage in developing these compounds as Alzheimer's imaging agent since the binding to amyloid fibrils prefers planar compounds. The splitting pattern of the methylene proton next to the amino group also showed significant coupling to the amino proton consistent with the notion of the existence of slow exchange and hydrogen bond in the ortho-substituted compounds. This is further verified by density functional theory (DFT) calculations which yielded a near planar low energy conformer for all the o-aminophenyl benzothiazoles and displayed a hydrogen bond from the amine proton to the nitrogen of the thiazole ring. A detailed analysis of the 1 H, 13 C, and 15 N NMR chemical shifts and DFT calculated structures of the compounds are described.

Heteronuclear NMR spectroscopic investigations of hydrogen bonding in 2-(benzo[d]thiazole-2′-yl)-N -alkylanilines

“…After addition of D 2 O, this peak reduced significantly because of the exchange of this proton to a deuterium (Table ). The 13 C NMR showed only minor chemical shift changes, as observed previously . The 15 N NMR chemical shift before and after the addition of D 2 O showed an upfield change of ~1 ppm, which is consistent with the exchange of a proton for a deuterium (Table ).…”

“…The compounds used in the present study were prepared and characterized using the procedures outlined in previous manuscripts . Structure, numbering, scheme, and IUPAC names for the synthesized compounds are shown in Table .…”

“…Although the 4‐(benzo[d]thiazole‐2′‐yl)‐ N ‐alkylanilines and its derivatives have been studied extensively, the 2‐(benzo[d]thiazole‐2′‐yl)‐ N ‐alkylanilines derivatives have not been described in the literature. Recently, we reported the synthesis and characterization of these analogs and demonstrated the presence of intramolecular hydrogen bonding in these 2‐aminophenyl benzothiazole compounds . The rationale for studying these derivatives stems from the fact that the presence of the intramolecular hydrogen bond may provide additional planarity to the molecule, which in turn should enhance binding to amyloid fibrils .…”