Structural studies of the inclusion compounds of α-naphthaleneacetic acid in heptakis(2,6-di-O-methyl)-β-Cyclodextrin and heptakis(2,3,6-tri-O-methyl)-β-Cyclodextrin by X-ray crystallography and molecular dynamics

The crystal structures of the inclusion compounds of α-naphthaleneacetic acid molecule (NAA) in heptakis(2,6-di-O-methyl)-β-Cyclodextrin (DM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-Cyclodextrin (TM-β-CD) are reported. The NAA/DM-β-CD inclusion complex crystallizes in the P212121 space group and its asymmetric unit contains two host molecules arranged co-axially in a head-to-tail mode, each one encapsulating one NAA guest molecule disordered over two distinct sites. One more NAA molecule is found outside the DM-β-CDs cavities, clathrated in the interstice between four neighboring hosts. The anhydrous complex units form screw channels deployed along the crystallographic a-axis. The NAA/TM-β-CD inclusion complex also crystallizes in the space group P212121. The guest molecule, disordered over two sites, is accommodated with its naphthyl group laying in the secondary rim of the host. The complexes stack along the a-axis forming columns and the crystal packing consists of antiparallel columns related by the b screw axis. The binding mode of the guest and the conformation of the host in these two inclusion complexes, is affected significantly by the guest molecular shape, the rigidity of the host macrocycle and the host–guest interactions reflecting the importance of the induced-fit process for inclusion complexation with methylated cyclodextrins. Furthermore, molecular dynamics simulations in explicit aqueous solvent show that in the absence of the crystal contacts the favored inclusion mode of NAA in both DM-β-CD and TM-β-CD host is the one with its naphthyl group laying equatorially in the host cavity and its carboxymethyl group pointing towards the primary host rim tethered by hydrogen bonds with methoxy or glucosidic oxygen atoms of the host.