Inclusion complexes of β-cyclodextrin with pyrazinamide and piperazine: Crystallographic and theoretical studies

The inclusion complexes of β-cyclodextrin (β-CD) with pyrazinamide (PYA) and piperazine (PIZ) have been investigated both in the solid phase by single-crystal X-ray diffraction analysis and in the gas phase by semi-empirical PM3 calculation. In the crystalline phase, the disordered PYA and PIZ molecules are entirely embedded in the β-CD cavity. The PYA pyrazine-centre displaces upwards by 1.15(1) Å from the β-CD plane, whereas the PIZ centre shifts downwards by 0.76(1) Å from the β-CD plane. The inclusion scenario changed in the gas phase. Two inclusion geometries of the PYA molecule are comparatively stable with binding energies of − 22.28 and − 25.29 kJ mol− 1: the pyrazine centre shifts upwards by 0.5 Å and downwards by 2.0 Å from the β-CD plane. The PIZ molecule positioning at 2.0 Å below the β-CD plane gives a more stable inclusion complex than does the PYA molecule by 22–25 kJ mol− 1. Structural distinction of the β-CD–PYA and β-CD–PIZ inclusion complexes in the solid phase (by X-ray crystallography) and gas phase (by PM3 calculation) is a paradigm of the CD conformational flexibility, the induced-fit mechanism and the dynamics of the inclusion process.