Rotational Barriers in N-methyl-cinnamoyl-chloroquine Analogues: Variable Temperature NMR Spectroscopy and DFT Studies

Abstract

The study of the rotational barrier of the amide bond (C(=O)− N) by nuclear magnetic resonance (NMR) and theoretical evaluation using the density functional theory (DFT) was investigated. Three new (E)-(3-((7-chloroquinolin-4-yl)amino)propyl)-N-methylacrylamides with variation of substitution on the aromatic ring were investigated. The dynamic NMR study shows restricted rotation around the amide bond resulting in the structures exhibiting a pair of rotamers (syn− and anti−). The reaction mechanism showing the formation of the tertiary acrylamide at room temperature from the reactant species was performed, using DFT/ M06−2X/ 6-311++G(d,p) method. Furthermore, the anti− and the syn− rotamers about the amide bond were investigated for each compound, using the same DFT method, to identify the relative stability of rotamers as well as the barrier height for their interconversion. The investigation was performed in different media, including vacuum, methanol, and aqueous media. The results suggest that the rotamers for each investigated molecule have minimal energy difference so that both the anti− and the syn− rotamers can be considered to co-exist in different media. An independent investigation of the secondary acrylamide suggests that the relative stability of the anti− and the syn− conformational rotamers favour only the formation of the anti–rotamer.