Halide Anion Recognition in Water by an Hexaprotonated Octaaza-Cryptand: A Molecular Dynamics Investigation Pierre Jost, Rachel Schurhammer, and Georges Wipff* [a] Abstract: Based on molecular dynamics simulations, we describe the F  versus Cl  complexation by an hexaprotonated cryptand L 6 in aqueous solution, in order to elucidate their structures, sol- vation properties and the status of external halide counterions. In water, F  and Cl  simulated inclusive com- plexes adopt a structure somewhat dif- ferent from the solid state structure of the F  complex : The anion binding involves two diammonium bridges only, and the accompanying counterions are dissociated from the  5 charged com- plex. A remarkable result is obtained for the dissociated L 6 ,3F  ,3Cl  system, where spontaneous complexation of F  the anion which forms the most stable complex with L 6 ) takes place during the dynamics. The resulting complex is of facial type; this suggests that the equili- brium involves multiple binding modes and structures in aqueous solution. The question of F  /Cl  binding selectivity is investigated by free energy perturba- tions simulations which nicely reproduce the spectacular preference for F  over Cl  . Two different methodologies used for the treatment of electrostatics standard versus Ewald calculations) yield similar conclusions. Keywords: counterions ´ electro- lytes ´ macrocycles ´ molecular dynamics ´ molecular recognition Introduction Anion binding by macrocyclic hosts, early identified as a founding theme of supramolecular chemistry, [1±4] received relatively little attention, compared with cation binding. [5±8] The main reasons are presumably the limited choice of anion- binding sites hydrogen bonds or Lewis acids), the larger size of the anions, and the role of solvent. In water, anions may be complexed by topologically connected macropoly)cyclic ligands, whose ammonium-binding sites are positively charg- ed, providing therefore, in addition to hydrogen bonding interactions, a strong electrostatic driving force for anion encapsulation. As far as modelling studies are concerned, the field of anion complexation is relatively unexplored. A recent review can be found in ref. [9] . Some molecular mechanics studies dealt with the gas phase behavior of these com- plexes, [10±13] while molecular dynamics MD) simulations with explicit solvent tackled the question of competitive hydration and complexation processes. [10±12] The first paper on ion recognition in solution by a macrocyclic host concerned the Cl  /Br  binding by a tetraprotonated SC24,4H 4 tricyclic host. [13] For this system, the energy profile for Cl  anion inclusion has also been investigated by molecular mechanics in the gas phase, [14] as well as by MD in aqueous solution. [15, 16] Halide anion complexation by a neutral calixarene in organic solution has recently been reported. [17] This paper deals with the halide anion complexation by an hexaprotonated bicyclic octaaza-cryptand Figure 1), studied experimentally by Lehn et al. [18, 19] This ligand, referred to later as L 6 , forms in acidic aqueous solution, a complex with F  of high stability logK  10.55, according to Lehn et al. [18] and 11.2 acording to Smith et al. [20] ) and displays a spectacular F  /Cl  selectivity > 10 8 ). The inclusive nature of the F  complex, noted hereafter as LF 5 , is supported by NMR spectroscopy in solution, and by an X-ray structure, [18] where the six ammonium N  sites form a quasi trigonal prismatic arrangement with F  ´´´ N  distances ranging from 2.76 to Figure 1. Schematic representation of the inclusion halide complex of L 6 left) with atomic charges and AMBER atom types used for the simulations right). [a] Prof. G. Wipff,P. Jost, R. Schurhammer Laboratoire MSM, UMR 7551 CNRS, Institut de Chimie 4, rue B. Pascal, 67000 Strasbourg France) E-mail: wipff@chimie.u-strasbg.fr Supporting information for this article is available on the WWW under http://www.wiley-vch.de/home/chemistry/ or from the author. FULL PAPER Chem. Eur. J. 2000, 6, No. 23  WILEY-VCH VerlagGmbH, D-69451 Weinheim, 2000 0947-6539/00/0623-4257 $ 17.50+.50/0 4257