Molecular model of CENS piperidine β-CD inclusion complex: DFT study

Abstract Structural aspects of the complexation of N-nitroso-N’-(2-chloroethyl)-N’-sulfamide piperidine (CENS) with β-cyclodextrin (β-CD) were investigated using standard B3LYP and MPW1PW91 Density Functional Theory (DFT) calculations. Two orientations of the incoming CENS inside β-CD were considered to determine the lowest energy complex, namely the head (ring first) and tail (chain first) orientations. The calculations confirm that the tail orientation is more favorable than the head one by 5.9 kcal/mol (B3LYP) and 5.9–6.1 kcal/mol (MPW1PW91) the driving factor being the deformation energy undergone by β-CD. This preference is also due to the fact that the complexation with tail orientation of CENS occurs with a favourable anti-parallel disposition of the dipole moments of β-CD and CENS. The computed structure for the CENS – β-CD complex is in good agreement with mass and 15 N NMR spectroscopy observations. Moreover, this complexation mode leads to the formation of four intermolecular H-bonds between CENS and CD, i.e. two conventional H-bonds, one between N atom (N136) of the NO bond of CENS and H 6 O atom (H129) of β-CD and the other one between O atom (O137) of CENS SO 2 group and H 6 O (H120) and two weak (C H…O) bonds. These interactions were investigated using the Natural Bond Orbital (NBO) approach.