Water Clusters DOI: 10.1002/anie.201106090 Supramolecular Encapsulation of Tetrahedrally Hydrated Guests in a Tetrahedron Host** Qi-Qiang Wang, Victor W. Day, and Kristin Bowman-James* In memory of George E. Walrafen Carefully designed molecular capsules can provide discrete microenvironments capable of trapping targeted guests inside their shielded cavities. [1] In so doing, they can stabilize reactive species, [2] capture reaction intermediates, [3] or collect multiple molecules to study interactions in a cleanroom-like environment. [4] While there are reports of elegant tetrahedral capsules based on transition metal frameworks, [5] tetrahedral covalent organic capsules comprised of a single molecule are noticeably lacking. [6] Herein we describe the synthesis of a tricyclic organic molecular capsule, 1, that provides an ideal docking site for tetrahedral hydrogen bond coordination. The capsule reproducibly incorporates a tetrahedron of water molecules that holds (solvates) a small guest inside, either a single molecule of water, H 2 O·4 H 2 O1, or a fluoride ion, F  ·4 H 2 O1. Essentially, the tetrahedrally positioned bridge- head amine hydrogen bonding sites promote the tetrahedral orientation of the solvation sphere. Almost 50 years ago Walrafen linked findings from physical data to the structure of the all-important liquid of life, water. He concluded that a very simple pentameric water network could account for many of the observed features in the Raman spectra. [7] The five-molecule unit, the “Walrafen pentamer”, takes advantage of the somewhat obvious four hydrogen bonding sites of a central water molecule through tetrahedral coordination to surrounding waters. This simple pentamer also represents the basic structure for solid water phases I h and I c , the two most common forms of ice, and probably for liquid water. [8] Since then, many groups have targeted the enigmatic water molecule, often focusing on small water clusters in order to model the more elusive structure of bulk water. [9, 10] Recently, an elegant example of a lone water molecule in the fullerene C 60 was reported. [11] However, such a tetrahedral array for a discrete pentamer cluster enclosed in a capsule-like host, [12, 13] has not previously been observed. Along a similar vein, the structural aspects of the aqueous solvation of molecules and ions have also spurred consider- able curiosity. Ions are especially of interest because the electrostatically generated molecule–ion interactions can compete with or add to the normally weaker hydrogen bond associations. Among other applications, a more quantitative assessment of these phenomena can lead to a better under- standing of the complexities of ion transport. Anion–water interactions have been less extensively studied, with the exception perhaps of aqueous clusters with halides X  ·n H 2 O. [14–16] Herein is reported an excellent dual-purpose model for both water and anion–water interactions, that has been captured in the crystalline state within the cleanroom- like environment of an organic capsule. The host 1 was synthesized by a simple three-step strategy (Scheme 1). Tris(2-aminoethyl)amine (2) was reacted with excess dimethyl 2,6-pyridinedicarboxylate (3) to give frag- ment 4, which was further reacted with excess 2 to produce 5. The final completion of the tetrahedron was achieved upon reacting 5 with three equivalents of 3. The tetrahedron 1 was Scheme 1. Synthesis of the covalent organic tetrahedral cage 1. [*] Dr. Q.-Q. Wang, Dr. V.W. Day, Prof. K. Bowman-James Department of Chemistry, University of Kansas 1251 Wescoe Hall Drive, Lawrence, KS 66045 (USA) E-mail: kbjames@ku.edu [**] We thank the National Science Foundation for support of this work (CHE-0854967) and for purchase of the X-ray diffractometer (CHE- 0923449). Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201106090. A ngewandte Chemi e 2119 Angew. Chem. Int. Ed. 2012, 51, 2119 –2123  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim