Interactions between cyclomaltoheptaose (beta-cyclodextrin, beta CD) and p-toluenesulfonyl chloride (TsCl) were investigated using MD simulations, both in vacuum, approximating the hydrophobic environment of the CD cavity, and with water as a solvent. In both cases, the minimum energy adiabatic paths, and the mean force potentials (MFP) for the insertion of TsCl along a reaction coordinate perpendicular to the CD plane, were calculated for the two possible orientations of TsCl. The results show a preferred entry of TsCl in the CD cavity with the sulfonyl chloride group pointing to the primary hydroxyls rim. In each orientation, two energy minima for the complex are detected in vacuum that reflect the H-H contacts between host and guest observed by NMR spectroscopy (ROESY, NOESY). These separate minima collapsed into a single broader minimum, when the solvent was introduced in the simulations. The resulting association constant between TsCl and beta CD (K-a approximate to 100 M-1) is in good agreement with the NMR results (K-a = 102 +/- 12 M-1) in deuterated water solution at 298 K. Advantage has been taken of the dynamics of the reagent inclusion to set up a one step process involving a transient Cu2+ chelate at the secondary hydroxyls rim position for the electrophilic monoactivation of beta CD at the primary hydroxyls rim using water as solvent.